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Samra YA, Abd El Salam ASG, Abdelghany AM, El-Shishtawy MM. Safranal-loaded gold nanoparticles alleviate hepatocellular carcinoma via targeting the Wnt/β-catenin pathway. Discov Oncol 2025; 16:821. [PMID: 40389761 PMCID: PMC12089598 DOI: 10.1007/s12672-025-02447-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 04/21/2025] [Indexed: 05/21/2025] Open
Abstract
BACKGROUND The Wnt/β-catenin pathway is frequently activated in hepatocellular carcinoma (HCC); thus, it is considered a potential target for novel therapies. Safranal (SAF), a natural product, is reputed for its antitumor and antioxidant activities. Gold nanoparticles (AuNPs) exhibit unique physicochemical properties, they can carry and transport drugs to the tumor as they can passively accumulate within the tumor. The current study aims to evaluate SAF and SAF-AuNPs antitumor effect in HCC model via targeting the Wnt pathway and to evaluate the ability of SAF-AuNPs and Doxorubicin-gold nanoparticles (DOX-AuNPs) in ameliorating DOX chemo-resistance in HCC and enhancing its therapeutic index to reduce unwanted side effects. RESULTS SAF significantly attenuated the Wnt/β-catenin pathway, which down-regulated the proliferation and tumor angiogenesis. SAF decreased significantly Wnt-3a, β-catenin, Cyclin D1 VEGF and MMP-9. Developing SAF-AuNPs enhanced the antitumor activity of SAF against HCC. Furthermore, SAF-AuNPs enhanced DOX-AuNPs antitumor activity and lowered multi-drug resistance (MDR) protein level, which attenuates DOX chemo-resistance. CONCLUSIONS We conclude that SAF and SAF-AuNPs are promising treatments for HCC. They have promising antitumor activity in addition to the ability to attenuate DOX chemo-resistance, so, the desired therapeutic effect may be obtained with minor doses and lowering the side effects.
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Affiliation(s)
- Yara A Samra
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, P.O. Box 35516, Mansoura, 35516, Egypt
| | - Al Shaima G Abd El Salam
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, P.O. Box 35516, Mansoura, 35516, Egypt
| | - Amr M Abdelghany
- Department of Spectroscopy, Physics Division, National Research Center, Giza, 12311, Egypt
- Basic Science Department, Horus University, Coastal Road, New Damietta, Egypt
| | - Mamdouh M El-Shishtawy
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, P.O. Box 35516, Mansoura, 35516, Egypt.
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Mandal M, Banerjee I, Mandal M. Effective approaches in conquering chemoresistance of glioblastoma: potential for nanoformulations. Drug Deliv Transl Res 2025:10.1007/s13346-025-01859-z. [PMID: 40259195 DOI: 10.1007/s13346-025-01859-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/10/2025] [Indexed: 04/23/2025]
Abstract
Glioblastoma Multiforme is an aggressive and complex cancer affecting mostly elderly patients above the age of 60 years. Originally classified as the fourth stage of glioma, it has an abysmal prognosis along with limited therapeutic options. Surgical removal of tumors, radiotherapy, and chemotherapy are prevalent treatment strategies with numerous therapeutic obstacles, including undefined boundary of tumor mass leaving traces even after excision, chances of secondary cancer formation, and presence of blood-brain barrier. These blood-brain and blood-brain tumor barriers actively restrict the permeability of many molecules from blood circulation to enter the central nervous system. Therefore, many conventional antineoplastic drugs fail to reach the tumor periphery except temozolomide. Meanwhile, active stem cells in the tumor microenvironment, genetic mutation inducing tumor growth, and epigenetic pattern alteration make this cancer chemoresistant. Our review delineates the recent approaches to resensitize the existing clinical drugs through specifically designed nanoformulations. Nanoparticles with modified physiological characteristics and modified through technological parameters can reduce the tumor's stemness, which increases tumor cells' apoptosis rate. Moreover, these nanoparticles can efficiently traverse the blood-brain barrier and escape from endosomal degradation with minimum toxicological impact. Overall, this review discusses the cancer chemoresistance phenomena and related pathways and highlights the potential of nanoformulation in reversing chemoresistance. Also, the existing limitations of this unique approach and suggestions are discussed at the end of the article, which may facilitate the identification of new directions for advancement of the nanoparticle-mediated reversal of chemoresistance.
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Affiliation(s)
- Madhurima Mandal
- School of Medical Science & Technology, Indian Institute of Technology, Kharagpur, West Bengal, 721302, India
| | - Indranil Banerjee
- Department of Pharmaceutical Technology, JIS University, 81, Nilgunj Road, Agarpara, Kolkata, West Bengal, 700109, India.
| | - Mahitosh Mandal
- School of Medical Science & Technology, Indian Institute of Technology, Kharagpur, West Bengal, 721302, India.
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Nanista EM, Poythress LE, Skipper IR, Haskins T, Cora MF, Rozario T. Anterior-posterior polarity signals differentially regulate regeneration-competence of the tapeworm Hymenolepis diminuta. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.11.642590. [PMID: 40161642 PMCID: PMC11952415 DOI: 10.1101/2025.03.11.642590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Competence to regenerate lost tissues varies widely across species. The rat tapeworm, Hymenolepis diminuta, undergoes continual cycles of shedding and regenerating thousands of reproductive segments to propagate the species. Despite its prowess, H. diminuta can only regenerate posteriorly from a singular tissue: the neck or germinative region (GR). What cells and signaling pathways restrict regeneration competence to the GR? In this study, we show that the head regulates regeneration-competence by promoting maintenance of the GR and inhibiting proglottid formation in a distance-dependent manner. Anterior-posterior (A-P) patterning within the GR provide local signals that mediate these head-dependent responses. βcat1 is necessary for stem cell maintenance, proliferation and proglottidization. On the other hand, sfrp is necessary for maintaining the GR at its proper length. Our study demonstrates that the head organizes a balance of pro- and anti-regeneration signals that must be integrated together and therefore control competence to regenerate.
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Pingping Z, Nan C, Yong T. Phytochemicals and their Nanoformulations for Overcoming Drug Resistance in Head and Neck Squamous Cell Carcinoma. Pharm Res 2025; 42:429-449. [PMID: 40032776 DOI: 10.1007/s11095-025-03836-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Accepted: 02/06/2025] [Indexed: 03/05/2025]
Abstract
BACKGROUND Drug resistance remains a significant challenge in the treatment of head and neck squamous cell carcinoma (HNSCC), leading to therapeutic failure and poor patient prognosis. Numerous mechanisms, including drug efflux pumps, altered tumor microenvironment (TME), and dysregulated cell death pathways, contribute to the development of resistance against conventional chemotherapeutic agents, immunotherapy, and targeted therapies. As resistance to traditional treatments continues to emerge, there is an urgent need for innovative therapeutic strategies to overcome these challenges. Phytochemicals are naturally occurring bioactive compounds and have demonstrated remarkable potential in targeting multiple resistance mechanisms simultaneously. METHOD This review comprehensively overviews the current understanding of drug resistance mechanisms in HNSCC and explores innovative strategies utilizing phytochemicals and their nanoformulations to overcome these resistance mechanisms, with a particular focus on recent developments and future perspectives in this field. RESULTS AND DISCUSSION Phytochemicals with anticancer properties include a wide range of herbal-derived molecules such as flavonoids, stilbenes, curcuminoids, alkaloids, traditional Chinese medicine, and others. These compounds can modulate ATP-binding cassette transporters, reverse epithelial-to-mesenchymal transition (EMT), target cancer stem cells (CSCs), and regulate various signaling pathways involved in drug resistance. The integration of phytochemicals into advanced nanoformulation systems has also shown a remarkable improvement in enhancing their bioavailability, stability, and targeted delivery to the TME, potentially improving their therapeutic efficacy. Furthermore, the combination of phytochemicals with conventional chemotherapeutic agents, targeted molecular therapy, and immune checkpoint inhibitors (ICIs) has exhibited synergistic effects, offering a promising approach to restoring drug sensitivity in resistant HNSCC cells. CONCLUSION Phytochemicals and their nanoformulations may improve response of HNSCC to therapy by alleviating drug resistance.
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Affiliation(s)
- Zhai Pingping
- Heilongjiang Academy of Chinese Medicine Sciences, Harbin, 150000, China
| | - Chen Nan
- Heilongjiang University of Chinese Medicine, Harbin, 150000, China
| | - Tang Yong
- Heilongjiang Academy of Chinese Medicine Sciences, Harbin, 150000, China.
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Kluz N, Kraj L, Chmiel P, Przybyłkowski AM, Wyrwicz L, Stec R, Szymański Ł. Correlation Between Antihypertensive Drugs and Survival Among Patients with Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2024; 16:3945. [PMID: 39682132 DOI: 10.3390/cancers16233945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 11/22/2024] [Accepted: 11/23/2024] [Indexed: 12/18/2024] Open
Abstract
There is a growing prevalence of pancreatic cancer, accompanied by accelerated disease progression and diminished survival rates. Radical resection with clear margins remains the sole viable option for achieving a long-term cure in patients. In cases of advanced, unresectable, and metastatic disease, chemotherapy based on leucovorin, 5-fluorouracil, irinotecan, oxaliplatin, gemcitabine, or nab-paclitaxel represents the cornerstone of the treatment. Considering the limited treatment options available following initial therapy, the strategy of repurposing commonly prescribed drugs such as antihypertensives into anti-cancer therapies in palliative treatment represents a promising avenue for enhancing survival in patients with pancreatic ductal adenocarcinoma. The repurposing of existing drugs is typically a more cost-effective and expedient strategy than the development of new ones. The potential for antihypertensive drugs to be employed as adjunctive therapies could facilitate a more comprehensive treatment approach by targeting multiple pathways involved in cancer progression and acquired resistance to treatment. Antihypertensive medications, particularly those belonging to the pharmacological classes of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and calcium channel blockers, are commonly prescribed and have well-established safety profiles, particularly among patients with pancreatic cancer who are affected by multiple comorbidities. Therefore, we emphasize the preclinical and clinical evidence supporting the use of antihypertensive agents in the treatment of pancreatic cancer, emphasizing their beneficial chemosensitizing effects.
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Affiliation(s)
- Natalia Kluz
- Department of Gastroenterology and Internal Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Leszek Kraj
- Department of Oncology, Medical University of Warsaw, 02-091 Warsaw, Poland
- Department of Molecular Biology, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, 05-552 Garbatka, Poland
| | - Paulina Chmiel
- Department of Molecular Biology, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, 05-552 Garbatka, Poland
| | - Adam M Przybyłkowski
- Department of Gastroenterology and Internal Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Lucjan Wyrwicz
- Department of Oncology and Radiotherapy, Maria Sklodowska-Curie National Cancer Research Institute, 02-781 Warsaw, Poland
| | - Rafał Stec
- Department of Oncology, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Łukasz Szymański
- Department of Molecular Biology, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, 05-552 Garbatka, Poland
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Zasheva D, Mladenov P, Zapryanova S, Gospodinova Z, Georgieva M, Alexandar I, Velinov V, Djilianov D, Moyankova D, Simova-Stoilova L. Cytotoxic Effects of Plant Secondary Metabolites and Naturally Occurring Bioactive Peptides on Breast Cancer Model Systems: Molecular Mechanisms. Molecules 2024; 29:5275. [PMID: 39598664 PMCID: PMC11596968 DOI: 10.3390/molecules29225275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 10/30/2024] [Accepted: 11/06/2024] [Indexed: 11/29/2024] Open
Abstract
Breast cancer is the second leading cause of death among women, and the number of mortal cases in diagnosed patients is constantly increasing. The search for new plant compounds with antitumor effects is very important because of the side effects of conventional therapy and the development of drug resistance in cancer cells. The use of plant substances in medicine has been well known for centuries, but the exact mechanism of their action is far from being elucidated. The molecular mechanisms of cytotoxicity exerted by secondary metabolites and bioactive peptides of plant origin on breast cancer cell lines are the subject of this review.
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Affiliation(s)
- Diana Zasheva
- Institute of Biology and Immunology of Reproduction, Bulgarian Academy of Sciences, Tsarigradsko Shosse, 73, 1113 Sofia, Bulgaria; (D.Z.); (S.Z.)
| | - Petko Mladenov
- Agrobioinstitute, Agricultural Academy, bul. “Dragan Tsankov” 8, 1164 Sofia, Bulgaria; (P.M.); (D.D.); (D.M.)
| | - Silvina Zapryanova
- Institute of Biology and Immunology of Reproduction, Bulgarian Academy of Sciences, Tsarigradsko Shosse, 73, 1113 Sofia, Bulgaria; (D.Z.); (S.Z.)
| | - Zlatina Gospodinova
- Institute of Plant Physiology and Genetics, Bulgarian Academy of Science, “Acad. Georgi Bonchev” Str., Bl. 21, 1113 Sofia, Bulgaria; (Z.G.); (M.G.); (V.V.)
| | - Mariyana Georgieva
- Institute of Plant Physiology and Genetics, Bulgarian Academy of Science, “Acad. Georgi Bonchev” Str., Bl. 21, 1113 Sofia, Bulgaria; (Z.G.); (M.G.); (V.V.)
| | - Irina Alexandar
- Institute of Molecular Biology “Rumen Tzanev”, Bulgarian Academy of Sciences, “Acad. Georgi Bonchev” Str., Bl. 21, 1113 Sofia, Bulgaria;
| | - Valentin Velinov
- Institute of Plant Physiology and Genetics, Bulgarian Academy of Science, “Acad. Georgi Bonchev” Str., Bl. 21, 1113 Sofia, Bulgaria; (Z.G.); (M.G.); (V.V.)
| | - Dimitar Djilianov
- Agrobioinstitute, Agricultural Academy, bul. “Dragan Tsankov” 8, 1164 Sofia, Bulgaria; (P.M.); (D.D.); (D.M.)
| | - Daniela Moyankova
- Agrobioinstitute, Agricultural Academy, bul. “Dragan Tsankov” 8, 1164 Sofia, Bulgaria; (P.M.); (D.D.); (D.M.)
| | - Lyudmila Simova-Stoilova
- Institute of Plant Physiology and Genetics, Bulgarian Academy of Science, “Acad. Georgi Bonchev” Str., Bl. 21, 1113 Sofia, Bulgaria; (Z.G.); (M.G.); (V.V.)
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Yu N, Wu Y, Wei Q, Li X, Li M, Wu W. m 6A modification of CDC5L promotes lung adenocarcinoma progression through transcriptionally regulating WNT7B expression. Am J Cancer Res 2024; 14:3565-3583. [PMID: 39113868 PMCID: PMC11301290 DOI: 10.62347/qhfa9669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 06/25/2024] [Indexed: 08/10/2024] Open
Abstract
Cell division cycle 5-like (CDC5L) protein is implicated in the development of various cancers. However, its role in the progression of lung adenocarcinoma (LUAD) remains uncertain. Our findings revealed frequent upregulation of CDC5L in LUAD, which correlated with poorer overall survival rates and advanced clinical stages. In vitro experiments demonstrated that CDC5L overexpression stimulated the proliferation, migration, and invasion of LUAD cells, whereas CDC5L knockdown exerted suppressive effects on these cellular processes. Furthermore, silencing CDC5L significantly inhibited tumor growth and metastasis in a xenograft mouse model. Mechanistically, CDC5L activates the Wnt/β-catenin signaling pathway by transcriptionally regulating WNT7B, thereby promoting LUAD progression. Besides, METTL14-mediated m6A modification contributed to CDC5L upregulation in an IGF2BP2-dependent manner. Collectively, our study uncovers a novel molecular mechanism by which the m6A-induced CDC5L functions as an oncogene in LUAD by activating the Wnt/β-catenin pathway through transcriptional regulation of WNT7B, suggesting that CDC5L may serve as a promising prognostic marker and therapeutic target for LUAD.
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Affiliation(s)
- Nanding Yu
- Department of Pulmonary and Critical Care Medicine, Fujian Medical University Union HospitalFuzhou 350001, Fujian, China
- Department of Geriatric Medicine, Fujian Medical University Union HospitalFuzhou 350001, Fujian, China
| | - Yingxiao Wu
- Department of Pulmonary and Critical Care Medicine, Fujian Medical University Union HospitalFuzhou 350001, Fujian, China
- Department of Geriatric Medicine, Fujian Medical University Union HospitalFuzhou 350001, Fujian, China
| | - Qiongying Wei
- Department of Pulmonary and Critical Care Medicine, Fujian Medical University Union HospitalFuzhou 350001, Fujian, China
- Department of Geriatric Medicine, Fujian Medical University Union HospitalFuzhou 350001, Fujian, China
| | - Xiaoping Li
- Department of Pulmonary and Critical Care Medicine, Fujian Medical University Union HospitalFuzhou 350001, Fujian, China
- Department of Geriatric Medicine, Fujian Medical University Union HospitalFuzhou 350001, Fujian, China
| | - Mengling Li
- Department of Pulmonary and Critical Care Medicine, Fujian Medical University Union HospitalFuzhou 350001, Fujian, China
- Department of Geriatric Medicine, Fujian Medical University Union HospitalFuzhou 350001, Fujian, China
| | - Weidong Wu
- Department of Thoracic Surgery, Fujian Medical University Union HospitalFuzhou 350001, Fujian, China
- Fujian Key Laboratory of Cardio-Thoracic Surgery, Fujian Medical UniversityFuzhou 350122, Fujian, China
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8
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Yu M, Qin K, Fan J, Zhao G, Zhao P, Zeng W, Chen C, Wang A, Wang Y, Zhong J, Zhu Y, Wagstaff W, Haydon RC, Luu HH, Ho S, Lee MJ, Strelzow J, Reid RR, He TC. The evolving roles of Wnt signaling in stem cell proliferation and differentiation, the development of human diseases, and therapeutic opportunities. Genes Dis 2024; 11:101026. [PMID: 38292186 PMCID: PMC10825312 DOI: 10.1016/j.gendis.2023.04.042] [Citation(s) in RCA: 34] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 03/18/2023] [Accepted: 04/12/2023] [Indexed: 02/01/2024] Open
Abstract
The evolutionarily conserved Wnt signaling pathway plays a central role in development and adult tissue homeostasis across species. Wnt proteins are secreted, lipid-modified signaling molecules that activate the canonical (β-catenin dependent) and non-canonical (β-catenin independent) Wnt signaling pathways. Cellular behaviors such as proliferation, differentiation, maturation, and proper body-axis specification are carried out by the canonical pathway, which is the best characterized of the known Wnt signaling paths. Wnt signaling has emerged as an important factor in stem cell biology and is known to affect the self-renewal of stem cells in various tissues. This includes but is not limited to embryonic, hematopoietic, mesenchymal, gut, neural, and epidermal stem cells. Wnt signaling has also been implicated in tumor cells that exhibit stem cell-like properties. Wnt signaling is crucial for bone formation and presents a potential target for the development of therapeutics for bone disorders. Not surprisingly, aberrant Wnt signaling is also associated with a wide variety of diseases, including cancer. Mutations of Wnt pathway members in cancer can lead to unchecked cell proliferation, epithelial-mesenchymal transition, and metastasis. Altogether, advances in the understanding of dysregulated Wnt signaling in disease have paved the way for the development of novel therapeutics that target components of the Wnt pathway. Beginning with a brief overview of the mechanisms of canonical and non-canonical Wnt, this review aims to summarize the current knowledge of Wnt signaling in stem cells, aberrations to the Wnt pathway associated with diseases, and novel therapeutics targeting the Wnt pathway in preclinical and clinical studies.
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Affiliation(s)
- Michael Yu
- School of Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Kevin Qin
- School of Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Jiaming Fan
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Ministry of Education Key Laboratory of Diagnostic Medicine, and Department of Clinical Biochemistry, The School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Guozhi Zhao
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Orthopedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Piao Zhao
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Orthopedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
- Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Wei Zeng
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Neurology, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong 523475, China
| | - Connie Chen
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Annie Wang
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Yonghui Wang
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Clinical Laboratory Medicine, Shanghai Jiaotong University School of Medicine, Shanghai 200000, China
| | - Jiamin Zhong
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Ministry of Education Key Laboratory of Diagnostic Medicine, and Department of Clinical Biochemistry, The School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Yi Zhu
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Orthopaedic Surgery, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - William Wagstaff
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Rex C. Haydon
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Hue H. Luu
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Sherwin Ho
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Michael J. Lee
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Jason Strelzow
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Russell R. Reid
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Laboratory of Craniofacial Suture Biology and Development, Department of Surgery Section of Plastic Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Tong-Chuan He
- Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Laboratory of Craniofacial Suture Biology and Development, Department of Surgery Section of Plastic Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA
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Zhang J, Jiang J, Liu H, Wang S, Ke K, Liu S, Jiang Y, Liu L, Gao X, He B, Su Y. BMP9 induces osteogenic differentiation through up-regulating LGR4 via the mTORC1/Stat3 pathway in mesenchymal stem cells. Genes Dis 2024; 11:101075. [PMID: 38292169 PMCID: PMC10825279 DOI: 10.1016/j.gendis.2023.101075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 06/21/2023] [Accepted: 07/24/2023] [Indexed: 02/01/2024] Open
Abstract
Bone defects and non-union are prevalent in clinical orthopedy, and the outcomes of current treatments are often suboptimal. Bone tissue engineering offers a promising approach to treating these conditions effectively. Bone morphogenetic protein 9 (BMP9) can commit mesenchymal stem cells to osteogenic lineage, and a knowledge of the underlying mechanisms may help advance the field of bone tissue engineering. Leucine-rich repeats containing G protein-coupled receptor 4 (LGR4), a member of G protein-coupled receptors, is essential for modulating bone development. This study is aimed at investigating the impact of LGR4 on BMP9-induced osteogenesis in mesenchymal stem cells as well as the underlying mechanisms. Bone marrow stromal cells from BMP9-knockout mice exhibited diminished LGR4 expression, and exogenous LGR4 clearly restored the impaired osteogenic potency of the bone marrow stromal cells. Furthermore, LGR4 expression was increased by BMP9 in C3H10T1/2 cells. LGR4 augmented the benefits of BMP9-induced osteogenic markers and bone formation, whereas LGR4 inhibition restricted these effects. Meanwhile, the BMP9-induced lipogenic markers were increased by LGR4 inhibition. The protein levels of Raptor and p-Stat3 were elevated by BMP9. Raptor knockdown or p-Stat3 suppression attenuated the osteoblastic markers and LGR4 expression brought on by BMP9. LGR4 significantly reversed the blocking effect of Raptor knockdown or p-Stat3 suppression on the BMP9-induced osteoblastic markers. Raptor interacts with p-Stat3, and p-Stat3 activates the LGR4 promoter activity. In conclusion, LGR4 boosts BMP9 osteoblastic potency in mesenchymal stem cells, and BMP9 may up-regulate LGR4 via the mTORC1/Stat3 signal activation.
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Affiliation(s)
- Jie Zhang
- Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing 400016, China
- Key Laboratory of Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing 400016, China
| | - Jinhai Jiang
- Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing 400016, China
- Key Laboratory of Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing 400016, China
| | - Hang Liu
- Key Laboratory of Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing 400016, China
- Department of Orthopedics, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Shiyu Wang
- Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing 400016, China
- Key Laboratory of Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing 400016, China
| | - Kaixin Ke
- Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing 400016, China
- Key Laboratory of Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing 400016, China
| | - Siyuan Liu
- Key Laboratory of Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing 400016, China
- Department of Orthopedics, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Yue Jiang
- Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing 400016, China
- Key Laboratory of Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing 400016, China
| | - Lu Liu
- Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing 400016, China
- Key Laboratory of Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing 400016, China
| | - Xiang Gao
- Key Laboratory of Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing 400016, China
- Department of Orthopedics, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Baicheng He
- Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing 400016, China
- Key Laboratory of Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing 400016, China
| | - Yuxi Su
- Orthopedics Department, Children's Hospital of Chongqing Medical University, Chongqing 400014, China
- China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Jiangxi Hospital Affiliated Children’s Hospital of Chongqing Medical University, Jiangxi 330000, China
- National Clinical Research Center for Child Health and Disorders, China
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10
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Lu X, Chen H, Zhang T. Solid pseudopapillary neoplasm (SPN) of the pancreas: current understanding on its malignant potential and management. Discov Oncol 2024; 15:77. [PMID: 38498246 PMCID: PMC10948659 DOI: 10.1007/s12672-024-00905-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 02/22/2024] [Indexed: 03/20/2024] Open
Abstract
Solid pseudopapillary neoplasms (SPN) of the pancreas are presently recognized as low-grade malignant tumors that are frequently observed in young females. This tumor has a low incidence and is associated with an excellent prognosis following surgical resection. Typical SPNs primarily affect the pancreas and tend to have moderate or asymptomatic manifestations. Based on retrospective research, it is anticipated that patients with SPN can achieve disease-free survival, even in cases when metastasis is detected during inspection. However, the incidence of malignant SPN has been consistently underestimated, as evidenced by recent research findings. Malignancy of SPN primarily encompasses invasion and infiltration, metastasis, and recurrence after R0 resection. Imaging technologies such as Ultrasound, Computed Tomography, Magnetic Resonance Imaging, and Position Emission Tomography are capable of preliminarily identifying malignant SPN, which is primarily based on its invasive clinical features. Research on risk factors of malignant SPN revealed that larger tumor size, Ki-67 index, and several other parameters had significant correlations with invasive tumor behavior. Pathologic features of malignant SPNs overlay other pancreatic tumors, nevertheless they can provide valuable assistance in the process of diagnosis. Several confirmed specific pathologic biomarkers are related to its cellular origin, characteristic gene mutation, and cell proliferation. Considering the invasiveness of malignant SPN, it is imperative to enhance the comprehensiveness of its therapy. Tumor resection remains a suggested course of action in line with typical SPN, and additional lymph node dissection is seen as reasonable. Compared to benign SPNs, malignant SPNs have worse prognosis, underscoring the necessity of early identification and treatment in comprehensive medical centers to get improved clinical outcomes.
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Affiliation(s)
- Xiaoyue Lu
- Peking Union Medical College, Beijing, China
| | - Hao Chen
- Department of General Surgery, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Beijing, China
| | - Taiping Zhang
- Department of General Surgery, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Beijing, China.
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11
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Chen Z, Lin B, Yao X, Weng J, Liu J, He Q, Song K, Zhou C, Zuo Z, Huang X, Liu Z, Huang Q, Xu Q, Guo X. Endothelial β-catenin upregulation and Y142 phosphorylation drive diabetic angiogenesis via upregulating KDR/HDAC9. Cell Commun Signal 2024; 22:182. [PMID: 38491522 PMCID: PMC10941375 DOI: 10.1186/s12964-024-01566-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 03/09/2024] [Indexed: 03/18/2024] Open
Abstract
BACKGROUND Diabetic angiogenesis is closely associated with disabilities and death caused by diabetic microvascular complications. Advanced glycation end products (AGEs) are abnormally accumulated in diabetic patients and are a key pathogenic factor for diabetic angiogenesis. The present study focuses on understanding the mechanisms underlying diabetic angiogenesis and identifying therapeutic targets based on these mechanisms. METHODS In this study, AGE-induced angiogenesis serves as a model to investigate the mechanisms underlying diabetic angiogensis. Mouse aortic rings, matrigel plugs, and HUVECs or 293T cells were employed as research objects to explore this pathological process by using transcriptomics, gene promoter reporter assays, virtual screening and so on. RESULTS Here, we found that AGEs activated Wnt/β-catenin signaling pathway and enhanced the β-catenin protein level by affecting the expression of β-catenin degradation-related genes, such as FZDs (Frizzled receptors), LRPs (LDL Receptor Related Proteins), and AXIN1. AGEs could also mediate β-catenin Y142 phosphorylation through VEGFR1 isoform5. These dual effects of AGEs elevated the nuclear translocation of β-catenin and sequentially induced the expression of KDR (Kinase Insert Domain Receptor) and HDAC9 (Histone Deacetylase 9) by POU5F1 and NANOG, respectively, thus mediating angiogenesis. Finally, through virtual screening, Bioymifi, an inhibitor that blocks VEGFR1 isoform5-β-catenin complex interaction and alleviates AGE-induced angiogenesis, was identified. CONCLUSION Collectively, this study offers insight into the pathophysiological functions of β-catenin in diabetic angiogenesis.
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Affiliation(s)
- Zhenfeng Chen
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Bingqi Lin
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Xiaodan Yao
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Jie Weng
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Jinlian Liu
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Qi He
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Ke Song
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Chuyu Zhou
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Zirui Zuo
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Xiaoxia Huang
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Zhuanhua Liu
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Qiaobing Huang
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Qiulin Xu
- Department of Intensive Care Unit, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Science, Southern Medical University, Guangzhou, 510515, China.
| | - Xiaohua Guo
- Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
- National Experimental Education Demonstration Center for Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
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12
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Karamad V, Sogutlu F, Ozkaya FC, Shademan B, Ebrahim W, El-Neketi M, Avci CB. Investigation of iso-propylchaetominine anticancer activity on apoptosis, cell cycle and Wnt signaling pathway in different cancer models. Fitoterapia 2024; 173:105789. [PMID: 38158162 DOI: 10.1016/j.fitote.2023.105789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 11/29/2023] [Accepted: 12/20/2023] [Indexed: 01/03/2024]
Abstract
Dysregulation of the Wnt signaling pathway contributes to the development of many cancer types. Natural compounds produced with biotechnological systems have been the focus of research for being a new drug candidate both with unlimited resources and cost-effective production. In this study, it was aimed to reveal the effects of isopropylchaetominine on cytotoxic, cytostatic, apoptotic and Wnt signaling pathways in brain, pancreatic and prostate cancer. The IC50 values of isopropylchaetominine in U-87 MG, PANC1, PC3 and LNCaP cells were calculated as 91.94 μM, 41.68 μM, 54.54 μM and 7.86 μM in 72nd h, respectively. The metabolite arrests the cell cycle in G0/G1 phase in each cancer cells. Iso-propylchaetominine induced a 4.3-fold and 1.9-fold increase in apoptosis in PC3 and PANC1 cells, respectively. The toxicity of isopropylchaetominine in healthy fibroblast cells was assessed using the annexin V method, and no significant apoptotic activity was observed between the groups treated with the active substance and untreated. In U-87 MG, PANC1, PC3, and LNCaP cells under treatment with isopropylchaetominin, the expression levels of DKK3, TLE1, AES, DKK1, FRZB, DAB2, AXIN1/2, PPARD, SFRP4, APC and SOX17 tumor suppressor genes increased significantly. Decreases in expression of Wnt1, Wnt2, Wnt3, Wnt4, Wnt5, Wnt6, Wnt10, Wnt11, FRZ2, FRZ3, FRZ7, TCF7L1, BCL9, PYGO, CCND2, c-MYC, WISP1 and CTNNB1 oncogenic genes were detected. All these result shows that isopropylchaetominine can present promising new treatment strategy in different cancer types.
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Affiliation(s)
- Vahidreza Karamad
- Department of Medical Biology, Faculty of Medicine, Ege University, Izmir 35100, Turkey
| | - Fatma Sogutlu
- Department of Medical Biology, Faculty of Medicine, Ege University, Izmir 35100, Turkey
| | - Ferhat Can Ozkaya
- Aliaga Industrial Zone Technology Transfer Office, Aliaga, İzmir 35800, Turkey
| | - Behrouz Shademan
- Stem cell Research Center, Tabriz University of Medical Sciences, Tabriz 51666-16471, Iran
| | - Weaam Ebrahim
- Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Mona El-Neketi
- Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
| | - Cigir Biray Avci
- Department of Medical Biology, Faculty of Medicine, Ege University, Izmir 35100, Turkey.
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13
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Gajos-Michniewicz A, Czyz M. WNT/β-catenin signaling in hepatocellular carcinoma: The aberrant activation, pathogenic roles, and therapeutic opportunities. Genes Dis 2024; 11:727-746. [PMID: 37692481 PMCID: PMC10491942 DOI: 10.1016/j.gendis.2023.02.050] [Citation(s) in RCA: 26] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 12/28/2022] [Accepted: 02/14/2023] [Indexed: 09/12/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a liver cancer, highly heterogeneous both at the histopathological and molecular levels. It arises from hepatocytes as the result of the accumulation of numerous genomic alterations in various signaling pathways, including canonical WNT/β-catenin, AKT/mTOR, MAPK pathways as well as signaling associated with telomere maintenance, p53/cell cycle regulation, epigenetic modifiers, and oxidative stress. The role of WNT/β-catenin signaling in liver homeostasis and regeneration is well established, whereas in development and progression of HCC is extensively studied. Herein, we review recent advances in our understanding of how WNT/β-catenin signaling facilitates the HCC development, acquisition of stemness features, metastasis, and resistance to treatment. We outline genetic and epigenetic alterations that lead to activated WNT/β-catenin signaling in HCC. We discuss the pivotal roles of CTNNB1 mutations, aberrantly expressed non-coding RNAs and complexity of crosstalk between WNT/β-catenin signaling and other signaling pathways as challenging or advantageous aspects of therapy development and molecular stratification of HCC patients for treatment.
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Affiliation(s)
- Anna Gajos-Michniewicz
- Department of Molecular Biology of Cancer, Medical University of Lodz, Lodz 92-215, Poland
| | - Malgorzata Czyz
- Department of Molecular Biology of Cancer, Medical University of Lodz, Lodz 92-215, Poland
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14
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Resendiz-Hernández M, García-Hernández AP, Silva-Cázares MB, Coronado-Uribe R, Hernández-de la Cruz ON, Arriaga-Pizano LA, Prieto-Chávez JL, Salinas-Vera YM, Ibarra-Sierra E, Ortiz-Martínez C, López-Camarillo C. MicroRNA-204 Regulates Angiogenesis and Vasculogenic Mimicry in CD44+/CD24- Breast Cancer Stem-like Cells. Noncoding RNA 2024; 10:14. [PMID: 38392969 PMCID: PMC10891775 DOI: 10.3390/ncrna10010014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 01/25/2024] [Accepted: 02/02/2024] [Indexed: 02/25/2024] Open
Abstract
Tumors have high requirements in terms of nutrients and oxygen. Angiogenesis is the classical mechanism for vessel formation. Tumoral vascularization has the function of nourishing the cancer cells to support tumor growth. Vasculogenic mimicry, a novel intratumoral microcirculation system, alludes to the ability of cancer cells to organize in three-dimensional (3D) channel-like architectures. It also supplies the tumors with nutrients and oxygen. Both mechanisms operate in a coordinated way; however, their functions in breast cancer stem-like cells and their regulation by microRNAs remain elusive. In the present study, we investigated the functional role of microRNA-204 (miR-204) on angiogenesis and vasculogenic mimicry in breast cancer stem-like cells. Using flow cytometry assays, we found that 86.1% of MDA-MB-231 and 92% of Hs-578t breast cancer cells showed the CD44+/CD24- immunophenotype representative of cancer stem-like cells (CSCs). The MDA-MB-231 subpopulation of CSCs exhibited the ability to form mammospheres, as expected. Interestingly, we found that the restoration of miR-204 expression in CSCs significantly inhibited the number and size of the mammospheres. Moreover, we found that MDA-MB-231 and Hs-578t CSCs efficiently undergo angiogenesis and hypoxia-induced vasculogenic mimicry in vitro. The transfection of precursor miR-204 in both CSCs was able to impair the angiogenesis in the HUVEC cell model, which was observed as a diminution in the number of polygons and sprouting cells. Remarkably, miR-204 mimics also resulted in the inhibition of vasculogenic mimicry formation in MDA-MB-231 and Hs-578t CSCs, with a significant reduction in the number of channel-like structures and branch points. Mechanistically, the effects of miR-204 were associated with a diminution of pro-angiogenic VEGFA and β-catenin protein levels. In conclusion, our findings indicated that miR-204 abrogates the angiogenesis and vasculogenic mimicry development in breast cancer stem-like cells, suggesting that it could be a potential tool for breast cancer intervention based on microRNA replacement therapies.
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Affiliation(s)
- Martha Resendiz-Hernández
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, CDMX 03100, Mexico; (M.R.-H.); (A.P.G.-H.); (O.N.H.-d.l.C.); (Y.M.S.-V.)
| | - Alejandra P. García-Hernández
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, CDMX 03100, Mexico; (M.R.-H.); (A.P.G.-H.); (O.N.H.-d.l.C.); (Y.M.S.-V.)
| | - Macrina B. Silva-Cázares
- Unidad Academica Multidisciplinaria Región Altiplano, Universidad Autónoma de San Luis Potosí, Matehuala 78760, San Luis Potosí, Mexico;
| | - Rogelio Coronado-Uribe
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, CDMX 03100, Mexico; (M.R.-H.); (A.P.G.-H.); (O.N.H.-d.l.C.); (Y.M.S.-V.)
| | - Olga N. Hernández-de la Cruz
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, CDMX 03100, Mexico; (M.R.-H.); (A.P.G.-H.); (O.N.H.-d.l.C.); (Y.M.S.-V.)
| | - Lourdes A. Arriaga-Pizano
- Unidad de Investigación Médica en Inmunoquímica, Hospital de Especialidades del Centro Médico Siglo XXI, Instituto Mexicano del Seguro Social, CDMX 06720, Mexico;
| | - Jessica L. Prieto-Chávez
- Laboratorio de Citometría de Flujo, Centro de Instrumentos, Coordinación de Investigación en Salud, Hospital de Especialidades del Centro Médico Siglo XXI, Instituto Mexicano del Seguro Social, CDMX 06720, Mexico;
| | - Yarely M. Salinas-Vera
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, CDMX 03100, Mexico; (M.R.-H.); (A.P.G.-H.); (O.N.H.-d.l.C.); (Y.M.S.-V.)
| | - Eloisa Ibarra-Sierra
- Departamento de Investigación, Instituto Estatal de Cancerologia “Dr. Arturo Beltrán Ortega”, Acapulco 39610, Guerrero, Mexico;
| | - Concepción Ortiz-Martínez
- Servicio de Ginecología Oncológica, Instituto Estatal de Cancerologia “Dr. Arturo Beltrán Ortega”, Acapulco 39610, Guerrero, Mexico;
| | - César López-Camarillo
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, CDMX 03100, Mexico; (M.R.-H.); (A.P.G.-H.); (O.N.H.-d.l.C.); (Y.M.S.-V.)
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15
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Xu X, Guo Y, Liu P, Zhang H, Wang Y, Li Z, Mei Y, Niu L, Liu R. Piezo Mediates the Mechanosensation and Injury-Repair of Pulpo-Dentinal Complex. Int Dent J 2024; 74:71-80. [PMID: 37833209 PMCID: PMC10829354 DOI: 10.1016/j.identj.2023.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 07/03/2023] [Accepted: 07/04/2023] [Indexed: 10/15/2023] Open
Abstract
OBJECTIVES The aim of this research was to investigate the functions of Piezo channels in dentin defect, including mechanical signalling and odontoblast responses. METHODS Rat dentin-defect models were constructed, and spatiotemporal expression of Piezo proteins was detected in the pulpo-dentinal complex. Real-time polymerase chain reaction (rtPCR) was used to investigate the functional expression pattern of Piezo channels in odontoblasts. Moreover, RNA interference technology was employed to uncover the underlying mechanisms of the Piezo-driven inflammatory response and repair under fluid shear stress (FSS) conditions in vitro. RESULTS Piezo1 and Piezo2 were found to be widely expressed in the odontoblast layer and dental pulp in the rat dentin-defect model during the end stage of reparative dentin formation. The expression levels of the Piezo1 and Piezo2 genes in MDPC-23 cells were high in the initial stage under FSS loading and then decreased over time. Moreover, the expression trends of inflammatory, odontogenic, and mineralisation genes were generally contrary to those of Piezo1 and Piezo2 over time. After silencing of Piezo1/Piezo2, FSS stimulation resulted in significantly higher expression of inflammatory, odontogenesis, and mineralisation genes in MDPC-23 cells. Finally, the expression of genes involved in the integrin β1/ERK1 and Wnt5b/β-catenin signalling pathways was changed in response to RNA silencing of Piezo1 and Piezo2. CONCLUSIONS Piezo1 and Piezo2 may be involved in regulating the expression of inflammatory and odontogenic genes in odontoblasts stimulated by FSS.
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Affiliation(s)
- Xiaoqiao Xu
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi' an, China
| | - Yi Guo
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi' an, China
| | - Peiqi Liu
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi' an, China
| | - Hui Zhang
- Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, China
| | - Yijie Wang
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi' an, China
| | - Zhen Li
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi' an, China
| | - Yukun Mei
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi' an, China
| | - Lin Niu
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi' an, China; Department of Prosthodontics, College of Stomatology, Xi'an Jiaotong University, Xi'an, China.
| | - Ruirui Liu
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, Xi' an, China; Department of Prosthodontics, College of Stomatology, Xi'an Jiaotong University, Xi'an, China.
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16
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Wang YM, Shen JT. Chitosan-based promising scaffolds for the construction of tailored nanosystems against osteoporosis: Current status and future prospects. J Appl Biomater Funct Mater 2024; 22:22808000241266487. [PMID: 39129376 DOI: 10.1177/22808000241266487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/13/2024] Open
Abstract
Despite advancements in therapeutic techniques, restoring bone tissue after damage remains a challenging task. Tissue engineering or targeted drug delivery solutions aim to meet the pressing clinical demand for treatment alternatives by creating substitute materials that imitate the structural and biological characteristics of healthy tissue. Polymers derived from natural sources typically exhibit enhanced biological compatibility and bioactivity when compared to manufactured polymers. Chitosan is a unique polysaccharide derived from chitin through deacetylation, offering biodegradability, biocompatibility, and antibacterial activity. Its cationic charge sets it apart from other polymers, making it a valuable resource for various applications. Modifications such as thiolation, alkylation, acetylation, or hydrophilic group incorporation can enhance chitosan's swelling behavior, cross-linking, adhesion, permeation, controllable drug release, enzyme inhibition, and antioxidative properties. Chitosan scaffolds possess considerable potential for utilization in several biological applications. An intriguing application is its use in the areas of drug distribution and bone tissue engineering. Due to their excellent biocompatibility and lack of toxicity, they are an optimal material for this particular usage. This article provides a comprehensive analysis of osteoporosis, including its pathophysiology, current treatment options, the utilization of natural polymers in disease management, and the potential use of chitosan scaffolds for drug delivery systems aimed at treating the condition.
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Affiliation(s)
- Ya-Ming Wang
- Department of Endocrine, Shengzhou People's Hospital (Shengzhou Branch of the First Affiliated Hospital of Zhejiang University School of Medicine, the Shengzhou Hospital of Shaoxing University), Shengzhou, Zhejiang, China
| | - Jiang-Tao Shen
- Department of Orthopedics, Shengzhou People's Hospital (Shengzhou Branch of the First Affiliated Hospital of Zhejiang University School of Medicine, the Shengzhou Hospital of Shaoxing University), Shengzhou, Zhejiang, China
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17
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Mazziotta C, Badiale G, Cervellera CF, Tognon M, Martini F, Rotondo JC. Regulatory mechanisms of circular RNAs during human mesenchymal stem cell osteogenic differentiation. Theranostics 2024; 14:143-158. [PMID: 38164139 PMCID: PMC10750202 DOI: 10.7150/thno.89066] [Citation(s) in RCA: 34] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 10/01/2023] [Indexed: 01/03/2024] Open
Abstract
Human osteogenic differentiation is a complex and well-orchestrated process which involves a plethora of molecular players and cellular processes. A growing number of studies have underlined that circular RNAs (circRNAs) play an important regulatory role during human osteogenic differentiation. CircRNAs are single-stranded, covalently closed non-coding RNA molecules that are acquiring increased attention as epigenetic regulators of gene expression. Given their intrinsic high conformational stability, abundance, and specificity, circRNAs can undertake various biological activities in order to regulate multiple cellular processes, including osteogenic differentiation. The most recent evidence indicates that circRNAs control human osteogenesis by preventing the inhibitory activity of miRNAs on their downstream target genes, using a competitive endogenous RNA mechanism. The aim of this review is to draw attention to the currently known regulatory mechanisms of circRNAs during human osteogenic differentiation. Specifically, we provide an understanding of recent advances in research conducted on various human mesenchymal stem cell types that underlined the importance of circRNAs in regulating osteogenesis. A comprehensive understanding of the underlying regulatory mechanisms of circRNA in osteogenesis will improve knowledge on the molecular processes of bone growth, resulting in the potential development of novel preclinical and clinical studies and the discovery of novel diagnostic and therapeutic tools for bone disorders.
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Affiliation(s)
- Chiara Mazziotta
- Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy
- Center for Studies on Gender Medicine - Department of Medical Sciences, University of Ferrara. 64/b, Fossato di Mortara Street. Ferrara, Italy
| | - Giada Badiale
- Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy
| | | | - Mauro Tognon
- Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy
| | - Fernanda Martini
- Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy
- Center for Studies on Gender Medicine - Department of Medical Sciences, University of Ferrara. 64/b, Fossato di Mortara Street. Ferrara, Italy
- Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy
| | - John Charles Rotondo
- Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy
- Center for Studies on Gender Medicine - Department of Medical Sciences, University of Ferrara. 64/b, Fossato di Mortara Street. Ferrara, Italy
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18
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Zhong C, Wang G, Guo M, Zhu N, Chen X, Yan Y, Li N, Yu W. The Role of Tumor Stem Cells in Colorectal Cancer Drug Resistance. Cancer Control 2024; 31:10732748241274196. [PMID: 39215442 PMCID: PMC11367616 DOI: 10.1177/10732748241274196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 07/09/2024] [Accepted: 07/23/2024] [Indexed: 09/04/2024] Open
Abstract
Background: Colorectal cancer is a major cause of mortality among the prevalent malignant tumors of the gastrointestinal tract. Although chemotherapy is a standard treatment for colorectal cancer, its efficacy is limited by chemoresistance. Recent studies have investigated targeting tumor stem cells as a potential new therapeutic approach for addressing chemoresistance in colorectal cancer. Colorectal cancer frequently relapses, with tumor stem cells often representing one of the leading causes of treatment failure. Purpose: Understanding drug resistance in colorectal cancer stem cells is crucial for improving treatment outcomes. By focusing on developing targeted therapies that specifically address drug resistance in colorectal cancer stem cells, there is potential to make significant advancements in the treatment of colorectal cancer.This approach may lead to more effective and lasting outcomes in patients battling colorectal cancer. Research Design: In this review, a comprehensive overview of recent research on colorectal cancer stem cell treatment resistance is presented.Results: Elucidating the key underlying mechanisms. This review also highlights the potential benefits of targeted therapies in overcoming colorectal cancer resistance to treatment. Conclusions: CCSCs are key players in drug resistance of CRC, indicating their potential as targets for effective therapy. Elucidating their role in this process could aid in discovering tailored treatment strategies.The significance of signaling pathways, TME, and miRNA in regulating drug resistance in CCSCs is been highlighted.
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Affiliation(s)
- Chen Zhong
- Jiangxi University of Chinese Medicine, Nanchang, China
| | - Guojuan Wang
- Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, China
| | - Min Guo
- Jiangxi University of Chinese Medicine, Nanchang, China
| | - Naicheng Zhu
- Jiangxi University of Chinese Medicine, Nanchang, China
| | - Xiudan Chen
- Jiangxi University of Chinese Medicine, Nanchang, China
| | - Yuwei Yan
- Jiangxi University of Chinese Medicine, Nanchang, China
| | - Nanxin Li
- Jiangxi University of Chinese Medicine, Nanchang, China
| | - Wenyan Yu
- Jiangxi University of Chinese Medicine, Nanchang, China
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Qin K, Yu M, Fan J, Wang H, Zhao P, Zhao G, Zeng W, Chen C, Wang Y, Wang A, Schwartz Z, Hong J, Song L, Wagstaff W, Haydon RC, Luu HH, Ho SH, Strelzow J, Reid RR, He TC, Shi LL. Canonical and noncanonical Wnt signaling: Multilayered mediators, signaling mechanisms and major signaling crosstalk. Genes Dis 2024; 11:103-134. [PMID: 37588235 PMCID: PMC10425814 DOI: 10.1016/j.gendis.2023.01.030] [Citation(s) in RCA: 55] [Impact Index Per Article: 55.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 11/01/2022] [Accepted: 01/29/2023] [Indexed: 08/18/2023] Open
Abstract
Wnt signaling plays a major role in regulating cell proliferation and differentiation. The Wnt ligands are a family of 19 secreted glycoproteins that mediate their signaling effects via binding to Frizzled receptors and LRP5/6 coreceptors and transducing the signal either through β-catenin in the canonical pathway or through a series of other proteins in the noncanonical pathway. Many of the individual components of both canonical and noncanonical Wnt signaling have additional functions throughout the body, establishing the complex interplay between Wnt signaling and other signaling pathways. This crosstalk between Wnt signaling and other pathways gives Wnt signaling a vital role in many cellular and organ processes. Dysregulation of this system has been implicated in many diseases affecting a wide array of organ systems, including cancer and embryological defects, and can even cause embryonic lethality. The complexity of this system and its interacting proteins have made Wnt signaling a target for many therapeutic treatments. However, both stimulatory and inhibitory treatments come with potential risks that need to be addressed. This review synthesized much of the current knowledge on the Wnt signaling pathway, beginning with the history of Wnt signaling. It thoroughly described the different variants of Wnt signaling, including canonical, noncanonical Wnt/PCP, and the noncanonical Wnt/Ca2+ pathway. Further description involved each of its components and their involvement in other cellular processes. Finally, this review explained the various other pathways and processes that crosstalk with Wnt signaling.
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Affiliation(s)
- Kevin Qin
- Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Michael Yu
- Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Jiaming Fan
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Ministry of Education Key Laboratory of Diagnostic Medicine, and Department of Clinical Biochemistry, The School of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Hongwei Wang
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Piao Zhao
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Departments of Orthopaedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Guozhi Zhao
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Departments of Orthopaedic Surgery and Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Wei Zeng
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Interventional Neurology, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong 523475, China
| | - Connie Chen
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Yonghui Wang
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Department of Clinical Laboratory Medicine, Shanghai Jiaotong University School of Medicine, Shanghai 200000, China
| | - Annie Wang
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Laboratory of Craniofacial Biology and Development, Department of Surgery Section of Plastic Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Zander Schwartz
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- School of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA
| | - Jeffrey Hong
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Lily Song
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - William Wagstaff
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Rex C. Haydon
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Hue H. Luu
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Sherwin H. Ho
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Jason Strelzow
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Russell R. Reid
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Laboratory of Craniofacial Biology and Development, Department of Surgery Section of Plastic Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Tong-Chuan He
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
- Laboratory of Craniofacial Biology and Development, Department of Surgery Section of Plastic Surgery, The University of Chicago Medical Center, Chicago, IL 60637, USA
| | - Lewis L. Shi
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL 60637, USA
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20
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He H, Wang S, Zhang W, Gao S, Guan H, Zhou P. Downregulation of TAB182 promotes cancer stem-like cell properties and therapeutic resistance in triple-negative breast cancer cells. BMC Cancer 2023; 23:1101. [PMID: 37953246 PMCID: PMC10642046 DOI: 10.1186/s12885-023-11552-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 10/20/2023] [Indexed: 11/14/2023] Open
Abstract
TAB182 participates in DNA damage repair and radio-/chemosensitivity regulation in various tumors, but its role in tumorigenesis and therapeutic resistance in breast cancer remains unclear. In the current paper, we observed that triple-negative Breast Cancer (TNBC), a highly aggressive type of breast cancer, exhibits a lower expression of TAB182. TAB182 knockdown stimulates the proliferation, migration, and invasion of TNBC cells. Our study first obtained RNA-seq data to explore the cellular functions mediated by TAB182 at the genome level in TNBC cells. A transcriptome analysis and in vitro experiments enabled us to identify that TAB182 downregulation drives the enhanced properties of cancer stem-like cells (CSCs) in TNBC cells. Furthermore, TAB182 deletion contributes to the resistance of cells to olaparib or cisplatin, which can be rescued by silencing GLI2, a gene downstream of cancer stemness-related signaling pathways. Our results reveal a novel function of TAB182 as a potential negative regulator of cancer stem-like properties and drug sensitivity in TNBC cells, suggesting that TAB182 may be a tumor suppressor gene and is associated with increased therapeutic benefits for TNBC patients.
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Affiliation(s)
- Huan He
- Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China
- NHC Key Laboratory of Radiobiology, School of Public Health, Jilin University, Changchun, 130021, People's Republic of China
| | - Shaozheng Wang
- Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China
| | - Wen Zhang
- Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China
| | - Shanshan Gao
- Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China
| | - Hua Guan
- Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China.
| | - Pingkun Zhou
- Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, People's Republic of China.
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21
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Amin MN, El-Far YM, El-Mowafy M, Elgaml A. Tazemetostat decreases β-catenin and CD13 protein expression in HEPG-2 and Hepatitis B virus-transfected HEPG-2 with decreased cell viability. Clin Epigenetics 2023; 15:180. [PMID: 37941056 PMCID: PMC10634085 DOI: 10.1186/s13148-023-01593-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 10/30/2023] [Indexed: 11/10/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the global health concerns. Hepatitis B virus (HBV) is one of the major causes of HCC. Poor clinical outcome of HCC patients is attributed to a small population of cancer cells known as cancer stem cells (CSCs). In this work, we studied the effect of inhibiting the enhancer of zeste homologue 2 (EZH2), a histone methyltransferase known to be overexpressed in CSCs, using tazemetostat (Taz). The effect of Taz was assessed in the HCC cell line (HEPG2) and Hepatitis B virus-transfected HEPG2 (HBV/HEPG2) cells. MTT assay showed a significant decrease in HEPG2 cells viability after 48 h treatment with either 0.5, 1, 4 or 6 μM Taz. HEPG2 and HBV/HEPG2 cells were incubated with either 0.5 or 1 μM Taz for 48 h, and then, the cells and supernatants were collected for protein expression analysis of EZH2, CD13, epithelial cell adhesion molecule (EpCAM) and β-catenin using enzyme-linked immunosorbent assay (ELISA). Taz showed a significant dose-dependent inhibition of EZH2, CD13 and β-catenin in HEPG2 and HBV/HEPG2 cells. Also, EpCAM protein levels were significantly decreased in HBV/HEPG2 but not in HEPG2 cell line alone. Our results indicate that Taz inhibition of EZH2 leads to downregulation of β-catenin signaling and eventually decreased expression of CD13 and EpCAM, which are characteristic for CSCs. The present study suggests that Taz could be a promising treatment for HCC including HBV-induced HCC that might be used in combination with radio/chemotherapy to target CSCs and prevent tumor relapse.
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Affiliation(s)
- Mohamed N Amin
- Biochemistry Department, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
| | - Yousra M El-Far
- Biochemistry Department, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
| | - Mohammed El-Mowafy
- Microbiology and Immunology Department, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
| | - Abdelaziz Elgaml
- Microbiology and Immunology Department, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
- Microbiology and Immunology Department, Faculty of Pharmacy, Horus University, New Damietta, 34518, Egypt.
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22
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Cui Y, Tang C, Guo J, Sun Y, Ke Z. Dishevelled Segment Polarity Protein 3: A Novel Prognosis-related Marker in Pan-driver-gene-negative Lung Adenocarcinoma. J Cancer 2023; 14:3028-3038. [PMID: 37859822 PMCID: PMC10583592 DOI: 10.7150/jca.87722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 08/30/2023] [Indexed: 10/21/2023] Open
Abstract
Purpose: In this study, we aimed to investigate the potential prognostic molecular marker in patients with "pan-driver-gene-negative" lung adenocarcinoma (PDGN-LUAD). LUAD patients who were negative for mutations in EGFR, KRAS, BRAF, HER2, MET, ALK, RET and ROS1 were identified as PDGN-LUAD. Methods: In the screening phase, we profiled the mRNA expression levels in 52 paired PDGN-LUAD tumor tissues and adjacent normal tissues using a genome-wide microarray, and the results revealed that the expression level of dishevelled segment polarity protein 3 (DVL3) was higher in PDGN-LUAD tumor tissues than in normal lung tissues. Then, we enrolled 626 PDGN-LUAD patients from three independent hospital centers and divided them into a training cohort, an internal validation cohort and two external validation cohorts. In the training cohort, tissue microarrays (TMAs) were used to confirm the protein expression level of DVL3. Statistical methods were applied to explore the prognostic role of DVL3. Results: The results indicated that the level of DVL3 could be used to classify patients with PDGN-LUAD in the training cohort into a high-risk group (high expression level of DVL3) and a low-risk group (low expression level of DVL3). In the training cohort, high-risk patients had shorter overall survival (OS) times (hazard ratio [HR] 2.27; 95% CI, 1.57-2.97; p<0.001) than low-risk patients. In the validation phase, the performance of DVL3 as a prognostic marker was successfully validated in the internal and external cohorts. Conclusions: In conclusion, DVL3 is an important prognostic indicator for PDGN-LUAD and may provide new insights into the treatment of PDGN-LUAD.
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Affiliation(s)
- Yongmei Cui
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China
| | - Cuilan Tang
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China
| | - Jinrui Guo
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China
| | - Yu Sun
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China
| | - Zunfu Ke
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China
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23
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Houser JS, Patel M, Wright K, Onopiuk M, Tsiokas L, Humphrey MB. The inhibitor of MyoD Family A (I-MFA) regulates megakaryocyte lineage commitment and terminal differentiation. Blood Cells Mol Dis 2023; 102:102760. [PMID: 37267696 DOI: 10.1016/j.bcmd.2023.102760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 05/22/2023] [Accepted: 05/23/2023] [Indexed: 06/04/2023]
Abstract
Hematopoiesis and lineage commitment are regulated by several conserved cell-intrinsic signaling pathways, including MAPKs and β-catenin/TCF/LEF. The Inhibitor of MyoD Family A (I-MFA), a transcriptional repressor and tumor suppressor gene, interacts with these pathways and is dysregulated in chronic and acute myeloid leukemias, suggesting it may play a role in development and differentiation during hematopoiesis. To study this, immune cell populations in the bone marrow (BM) and periphery were analyzed in mice lacking Mdfi, encoding I-MFA (I-MFA-/-), and wild type (WT) controls. I-MFA-/- mice had reduced spleen and BM cellularity, with significant hyposplenism, compared to WT mice. In blood, total red blood cells and platelet counts were significantly reduced in I-MFA-/- mice, accompanied by a reduction in megakaryocyte (MK)/erythrocyte progenitor cells and an increase in myeloid progenitors in BM compared to WT mice. The K562 cell line exhibits PMA-induced MK differentiation, and shRNA knockdown of I-MFA resulted in reduced differentiation compared to control, with an increase and prolongation in phospho-JNK and phospho-ERK signaling. Overexpression of I-MFA promoted MK differentiation. These results suggest I-MFA plays a cell-intrinsic role in the response to differentiation signals, an effect that can be explored in the context of hematological cancers or other blood proliferative disorders.
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Affiliation(s)
- Jeremy S Houser
- Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America
| | - Maulin Patel
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America
| | - Kyle Wright
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America
| | - Marta Onopiuk
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America
| | - Leonidas Tsiokas
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America
| | - Mary Beth Humphrey
- Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America; Oklahoma City Veteran's Affairs Medical Center, Oklahoma City, OK, United States of America.
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Dai J, Hao Y, Chen X, Yu Q, Wang B. miR‑122/SENP1 axis confers stemness and chemoresistance to liver cancer through Wnt/β‑catenin signaling. Oncol Lett 2023; 26:390. [PMID: 37559577 PMCID: PMC10407855 DOI: 10.3892/ol.2023.13976] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 06/22/2023] [Indexed: 08/11/2023] Open
Abstract
The property of inherent stemness of tumor cells coupled with the development of chemoresistance results in a poor prognosis for patients with liver cancer. Therefore, the present study focused on microRNA (miR)-122, a potential tumor suppressor, the expression of which has been previously shown to be significantly decreased and negatively associated with cancer cell stemness in liver cancer. The present study aimed to identify the molecular targets of miR-122 whilst uncovering the mechanism underlying chemoresistance and stemness of HepG2 cells in liver cancer. Bioinformatics online tools, such as ENCORI, coupled with dual-luciferase reporter assays in HepG2 cells, were used to identify and validate small ubiquitin-like modifier (SUMO) specific peptidase 1 (SENP1) as a potential target of miR-122 in liver cancer. The liver cancer stem cell population was determined using sphere formation assays and flow cytometry, whilst stem cell markers (Oct3/4, Nanog, B lymphoma Mo-MLV insertion region 1 homolog and Notch1) were detected by reverse transcription-quantitative PCR. Chemoresistance, cell proliferation and migratory ability of HepG2 cells were monitored using Cell Counting Kit-8, colony formation and Transwell assays, respectively. The overexpression of miR-122 by mimic transfection led to a significant decrease in the number spheres, downregulation of stem cell marker expression, the number of CD24+ cells, drug-resistance protein levels (P-glycoprotein and multidrug resistance protein), impaired chemoresistance, proliferation and migration of HepG2 cells. The transfection of SENP1 overexpression vector resulted in contrasting functions to miR-122 mimics, by partially reversing the effects induced by miR-122 mimic transfection in HepG2 cells. Wnt/β-catenin signaling has been proven to be involved in cancer stemness and malignant behavior. Western blotting analysis in HepG2 cells showed that the expression levels of both Wnt1 and β-catenin were significantly reduced after overexpressing miR-122, but increased after overexpressing SENP1. Co-transfection with the SENP1 overexpression vector reversed the suppression induced by the miR-122 mimics on Wnt1 and β-catenin expression. Co-immunoprecipitation, SUMOylation and half-life assays showed SENP1 interacted with β-catenin and decreased the SUMOylation of β-catenin, thereby enhancing its stability. Finally, tumor xenograft analyses revealed that HepG2 cells transfected with Agomir-122 exerted significantly lower tumor initiation frequency and growth rate, and a superior response to DOX in vivo, compared with those transfected with Agomir NC. Taken together, data from the present study miR-122/SENP1 axis can regulate β-catenin stability through de-SUMOylation, thereby promoting stemness and chemoresistance in liver cancer.
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Affiliation(s)
- Jianbo Dai
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400060, P.R. China
- Department of General Surgery, Nan'an District People's Hospital of Chongqing, Chongqing 400060, P.R. China
| | - Yaqin Hao
- Department of Gastroenterology, The Fifth People's Hospital of Chongqing, Chongqing 400060, P.R. China
| | - Xun Chen
- Department of Anesthesiology, Nan'an District People's Hospital of Chongqing, Chongqing 400060, P.R. China
| | - Qingsan Yu
- Department of General Surgery, Nan'an District People's Hospital of Chongqing, Chongqing 400060, P.R. China
| | - Bin Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400060, P.R. China
- Department of General Surgery, Chongqing Hospital of Integrated Traditional Chinese and Western Medicine, Chongqing 400060, P.R. China
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Zhao P, Sun L, Zhao C. TCF1/LEF1 triggers Wnt-dependent chemokine/cytokine-induced inflammation and cadherin pathways to drive T-ALL cell migration. Biochem Biophys Rep 2023; 34:101457. [PMID: 36942321 PMCID: PMC10024088 DOI: 10.1016/j.bbrep.2023.101457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 03/09/2023] [Indexed: 03/14/2023] Open
Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is a type of aggressive hematologic malignancy. It progresses quickly and it is likely to be fatal within a few months without treatment. Despite the limitations of current clinical therapies, there is an urgent need for novel and targeted therapies. To explore potential targeted therapies, molecular genetic mechanisms of T-ALL metastasis must be uncovered. However, the genes and mechanisms that mediate T-ALL metastasis are largely unknown. Recent insights into T-ALL biology have identified several genes that can be grouped into several targetable signaling pathways. The Wnt/β-catenin signaling pathway is one of the most important pathways. Our work investigated the functions of TCF1 and LEF1 in cell growth and migration mediated by the Wnt signaling pathway. We found that TCF1 and LEF1 knockdown weakly repressed T-ALL cell proliferation but distinctly impaired cell migration. T-ALL metastasis is dependent on cell migration and invasion. Our results displayed that TCF1 and LEF1 regulated T-ALL cell migration by the Wnt-dependent chemokine and cytokine-induced inflammation and cadherin signaling pathways. By transcriptionally regulating these pathways-associated genes, TCF1 and LEF1 inhibited cell adhesion and promoted cell migration and invasion.
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Affiliation(s)
- Pin Zhao
- Department of Clinical Laboratory, National Clinical Research Center for Infectious Diseases, The Third People's Hospital of Shenzhen, Southern University of Science and Technology, 29th Bulan Road, Longgang District, Shenzhen, 518112, China
- Corresponding author.
| | - Lanming Sun
- Department of Prevention, Health Care and Fertility, Xinfuli Community Hospital, Linhongnong Road, Dahongmen, Fengtai District, Beijing, 100068, China
| | - Cong Zhao
- Department of Prevention, Health Care and Fertility, Xinfuli Community Hospital, Linhongnong Road, Dahongmen, Fengtai District, Beijing, 100068, China
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26
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Wang W, Rana PS, Markovic V, Sossey-Alaoui K. The WAVE3/β-catenin oncogenic signaling regulates chemoresistance in triple negative breast cancer. Breast Cancer Res 2023; 25:31. [PMID: 36949468 PMCID: PMC10035207 DOI: 10.1186/s13058-023-01634-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 03/06/2023] [Indexed: 03/24/2023] Open
Abstract
BACKGROUND Metastatic breast cancer is responsible for the death of the majority of breast cancer patients. In fact, metastatic BC is the 2nd leading cause of cancer-related deaths in women in the USA and worldwide. Triple negative breast cancer (TNBC), which lacks expression of hormone receptors (ER-α and PR) and ErbB2/HER2, is especially lethal due to its highly metastatic behavior, propensity to recur rapidly, and for its resistance to standard of care therapies, through mechanisms that remain incompletely understood. WAVE3 has been established as a promoter of TNBC development and metastatic progression. In this study, we investigated the molecular mechanisms whereby WAVE3 promotes therapy-resistance and cancer stemness in TNBC, through the regulation of β-catenin stabilization. METHODS The Cancer Genome Atlas dataset was used to assess the expression of WAVE3 and β-catenin in breast cancer tumors. Kaplan-Meier Plotter analysis was used to correlate expression of WAVE3 and β-catenin with breast cancer patients' survival probability. MTT assay was used to quantify cell survival. CRISPR/Cas9-mediated gene editing, 2D and 3D tumorsphere growth and invasion assays, Immunofluorescence, Western blotting, Semi-quantitative and real-time quantitative PCR analyses were applied to study the WAVE3/β-catenin oncogenic signaling in TNBC. Tumor xenograft assays were used to study the role of WAVE3 in mediating chemotherapy resistance of TNBC tumors. RESULTS Genetic inactivation of WAVE3 in combination of chemotherapy resulted in inhibition of 2D growth and 3D tumorsphere formation and invasion of TNBC cells in vitro, as well as tumor growth and metastasis in vivo. In addition, while re-expression of phospho-active WAVE3 in the WAVE3-deficient TNBC cells restored the oncogenic activity of WAVE3, re-expression of phospho-mutant WAVE3 did not. Further studies revealed that dual blocking of WAVE3 expression or phosphorylation in combination with chemotherapy treatment inhibited the activity and expression and stabilization of β-catenin. Most importantly, the combination of WAVE3-deficiency or WAVE3-phospho-deficiency and chemotherapy suppressed the oncogenic behavior of chemoresistant TNBC cells, both in vitro and in vivo. CONCLUSION We identified a novel WAVE3/β-catenin oncogenic signaling axis that modulates chemoresistance of TNBC. This study suggests that a targeted therapeutic strategy against WAVE3 could be effective for the treatment of chemoresistant TNBC tumors.
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Affiliation(s)
- Wei Wang
- Department of Medicine, MetroHealth Medical Center, Cleveland, OH, 44109, USA
- Case Western Reserve University School of Medicine, Case Western Reserve University, Cleveland, OH, 44016, USA
| | - Priyanka S Rana
- Department of Medicine, MetroHealth Medical Center, Cleveland, OH, 44109, USA
- Case Western Reserve University School of Medicine, Case Western Reserve University, Cleveland, OH, 44016, USA
| | - Vesna Markovic
- Case Western Reserve University School of Medicine, Case Western Reserve University, Cleveland, OH, 44016, USA
| | - Khalid Sossey-Alaoui
- Department of Medicine, MetroHealth Medical Center, Cleveland, OH, 44109, USA.
- Case Western Reserve University School of Medicine, Case Western Reserve University, Cleveland, OH, 44016, USA.
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, 44106, USA.
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27
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Yang Q, Al-Hendy A. Update on the Role and Regulatory Mechanism of Extracellular Matrix in the Pathogenesis of Uterine Fibroids. Int J Mol Sci 2023; 24:5778. [PMID: 36982852 PMCID: PMC10051203 DOI: 10.3390/ijms24065778] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 02/22/2023] [Accepted: 03/08/2023] [Indexed: 03/30/2023] Open
Abstract
Uterine fibroids (UFs), also known as leiomyomas, are benign tumors of the myometrium affecting over 70% of women worldwide, particularly women of color. Although benign, UFs are associated with significant morbidity; they are the primary indication for hysterectomy and a major source of gynecologic and reproductive dysfunction, ranging from menorrhagia and pelvic pain to infertility, recurrent miscarriage, and preterm labor. So far, the molecular mechanisms underlying the pathogenesis of UFs are still quite limited. A knowledge gap needs to be filled to help develop novel strategies that will ultimately facilitate the development of therapies and improve UF patient outcomes. Excessive ECM accumulation and aberrant remodeling are crucial for fibrotic diseases and excessive ECM deposition is the central characteristics of UFs. This review summarizes the recent progress of ascertaining the biological functions and regulatory mechanisms in UFs, from the perspective of factors regulating ECM production, ECM-mediated signaling, and pharmacological drugs targeting ECM accumulation. In addition, we provide the current state of knowledge by discussing the molecular mechanisms underlying the regulation and emerging role of the extracellular matrix in the pathogenesis of UFs and in applications. Comprehensive and deeper insights into ECM-mediated alterations and interactions in cellular events will help develop novel strategies to treat patients with this common tumor.
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Affiliation(s)
- Qiwei Yang
- Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL 60637, USA;
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Su Y, Dang NM, Depypere H, Santucci-Pereira J, Gutiérrez-Díez PJ, Kanefsky J, Janssens JP, Russo J. Recombinant human chorionic gonadotropin induces signaling pathways towards cancer prevention in the breast of BRCA1/2 mutation carriers. Eur J Cancer Prev 2023; 32:126-138. [PMID: 35881946 PMCID: PMC9800649 DOI: 10.1097/cej.0000000000000763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Strategies for breast cancer prevention in women with germline BRCA1/2 mutations are limited. We previously showed that recombinant human chorionic gonadotropin (r-hCG) induces mammary gland differentiation and inhibits mammary tumorigenesis in rats. The present study investigated hCG-induced signaling pathways in the breast of young nulliparous women carrying germline BRCA1/2 mutations. METHODS We performed RNA-sequencing on breast tissues from 25 BRCA1/2 mutation carriers who received r-hCG treatment for 3 months in a phase II clinical trial, we analyzed the biological processes, reactome pathways, canonical pathways, and upstream regulators associated with genes differentially expressed after r-hCG treatment, and validated genes of interest. RESULTS We observed that r-hCG induces remarkable transcriptomic changes in the breast of BRCA1/2 carriers, especially in genes related to cell development, cell differentiation, cell cycle, apoptosis, DNA repair, chromatin remodeling, and G protein-coupled receptor signaling. We revealed that r-hCG inhibits Wnt/β-catenin signaling, MYC, HMGA1 , and HOTAIR , whereas activates TGFB/TGFBR-SMAD2/3/4, BRCA1, TP53, and upregulates BRCA1 protein. CONCLUSION Our data suggest that the use of r-hCG at young age may reduce the risk of breast cancer in BRCA1/2 carriers by inhibiting pathways associated with stem/progenitor cell maintenance and neoplastic transformation, whereas activating genes crucial for breast epithelial differentiation and lineage commitment, and DNA repair.
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Affiliation(s)
- Yanrong Su
- The Irma H Russo, MD, Breast Cancer Research Laboratory at the Fox Chase Cancer Center-Temple Health, 333 Cottman Avenue, Philadelphia, PA 19111, USA
- These authors contributed equally: Yanrong Su, Nhi M. Dang, and Herman Depypere
| | - Nhi M. Dang
- The Irma H Russo, MD, Breast Cancer Research Laboratory at the Fox Chase Cancer Center-Temple Health, 333 Cottman Avenue, Philadelphia, PA 19111, USA
- These authors contributed equally: Yanrong Su, Nhi M. Dang, and Herman Depypere
| | - Herman Depypere
- Department of Gynecology, Breast and Menopause clinic, University Hospital of Ghent, Corneel Heymanslaan 10, 9000 Ghent, Belgium
- These authors contributed equally: Yanrong Su, Nhi M. Dang, and Herman Depypere
| | - Julia Santucci-Pereira
- The Irma H Russo, MD, Breast Cancer Research Laboratory at the Fox Chase Cancer Center-Temple Health, 333 Cottman Avenue, Philadelphia, PA 19111, USA
| | | | - Joice Kanefsky
- The Irma H Russo, MD, Breast Cancer Research Laboratory at the Fox Chase Cancer Center-Temple Health, 333 Cottman Avenue, Philadelphia, PA 19111, USA
| | - Jaak Ph. Janssens
- European Cancer Prevention Organization, University of Hasselt, Klein Hilststraat 5, 3500 Hasselt, Belgium
| | - Jose Russo
- The Irma H Russo, MD, Breast Cancer Research Laboratory at the Fox Chase Cancer Center-Temple Health, 333 Cottman Avenue, Philadelphia, PA 19111, USA
- Dr. Russo conceived the study and supervised the work. Dr. Russo passed away on September 24, 2021
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Identification and Validation of Potentially Clinically Relevant CpG Regions within the Class 2 Tumor Suppressor Gene SFRP1 in Pancreatic Cancer. Cancers (Basel) 2023; 15:cancers15030683. [PMID: 36765639 PMCID: PMC9913221 DOI: 10.3390/cancers15030683] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/18/2023] [Accepted: 01/20/2023] [Indexed: 01/25/2023] Open
Abstract
In pancreatic cancer treatment, tumor stage-dependent chemotherapies are used to prolong overall survival. By measuring DNA promoter hypermethylation in the plasma of patients with stage IV pancreatic cancer, it was recently shown that promoter DNA methylation of the tumor suppressor gene SFRP1 has a high value for predicting failure of drug treatment with gemcitabine. In this study, we therefore aimed to identify as precisely as possible the region in the SFRP1 promoter that is frequently hypermethylated in pancreatic cancer tissue. First, we used the TCGA data set to define CpG-rich regions flanking the SFRP1 transcription start site that were significantly more methylated in pancreatic cancer compared to normal pancreatic acinar tissue. A core CpG island was identified that exhibited abundant tumor DNA methylation and anti-correlation of SFRP1 mRNA expression. To validate our in silico results, we performed bisulfide conversion followed by DNA pyrosequencing of 28 matched formalin-fixed, paraffin-embedded (FFPE) pancreatic cancer cases and six pancreatic cancer cell lines. A defined block of seven CpG sites within the core CpG island was identified, which confirmed our in silico results by showing significantly higher SFRP1 methylation in pancreatic cancer specimens than in normal pancreatic tissue. By selecting this core CpG island, we were able to determine a median overall survival benefit for the low SFRP1 methylation group compared to the high SFRP1 methylation group (702 versus 517 days, p = 0.01) in the TCGA pancreatic cancer cohort. We propose a compact pyrosequencing assay that can be used in the future to further investigate the prognostic value of SFRP1 promoter hypermethylation in predicting pancreatic cancer chemoresistance. Therefore, instead of DNA analysis from blood (liquid biopsy), DNA easily extractable from cancer tissue blocks (FFPE material) could be used.
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Chalcones: Promising therapeutic agents targeting key players and signaling pathways regulating the hallmarks of cancer. Chem Biol Interact 2023; 369:110297. [PMID: 36496109 DOI: 10.1016/j.cbi.2022.110297] [Citation(s) in RCA: 38] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 11/29/2022] [Accepted: 12/02/2022] [Indexed: 12/12/2022]
Abstract
The need for innovative anticancer treatments with high effectiveness and low toxicity is urgent due to the development of malignancies that are resistant to chemotherapeutic agents and the poor specificity of existing anticancer treatments. Chalcones are 1,3-diaryl-2-propen-1-ones, which are the precursors for flavonoids and isoflavonoids. Chalcones are readily available from a wide range of natural resources and consist of very basic chemical scaffolds. Because the ease with which the synthesis it allows for the production of several chalcone derivatives. Various in-vitro and in-vivo studies indicate that naturally occurring and synthetic chalcone derivatives exhibit promising biological activities against cancer hallmarks such as proliferation, angiogenesis, invasion, metastasis, inflammation, stemness, and regulation of cancer epigenetics. According to their structure and functional groups, chalcones derivatives and their hybrid compounds exert a broad range of biological activities through targeting key elements and signaling molecules relevant to cancer progression. This review will provide valuable insights into the latest updates of chalcone groups as anticancer agents and extensively discuss their underlying molecular mechanisms of action.
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Surya K, Manickam N, Jayachandran KS, Kandasamy M, Anusuyadevi M. Resveratrol Mediated Regulation of Hippocampal Neuroregenerative Plasticity via SIRT1 Pathway in Synergy with Wnt Signaling: Neurotherapeutic Implications to Mitigate Memory Loss in Alzheimer's Disease. J Alzheimers Dis 2023; 94:S125-S140. [PMID: 36463442 PMCID: PMC10473144 DOI: 10.3233/jad-220559] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Alzheimer's disease (AD) is a major form of dementia. Abnormal amyloidogenic event-mediated degeneration of cholinergic neurons in the cognitive centers of the brain has been attributed to neuropathological sequelae and behavioral deficits in AD. Besides, impaired adult neurogenesis in the hippocampus has experimentally been realized as an underlying cause of dementia regardless of neurodegeneration. Therefore, nourishing the neurogenic process in the hippocampus has been considered an effective therapeutic strategy to mitigate memory loss. In the physiological state, the Wnt pathway has been identified as a potent mitogenic generator in the hippocampal stem cell niche. However, downstream components of Wnt signaling have been noticed to be downregulated in AD brains. Resveratrol (RSV) is a potent Sirtuin1 (SIRT1) enhancer that facilitates neuroprotection and promotes neurogenesis in the hippocampus of the adult brain. While SIRT1 is an important positive regulator of Wnt signaling, ample reports indicate that RSV treatment strongly mediates the fate determination of stem cells through Wnt signaling. However, the possible therapeutic roles of RSV-mediated SIRT1 enhancement on the regulation of hippocampal neurogenesis and reversal of memory loss through the Wnt signaling pathway have not been addressed yet. Taken together, this review describes RSV-mediated effects on the regulation of hippocampal neurogenesis via the activation of SIRT1 in synergy with the Wnt signaling. Further, the article emphasizes a hypothesis that RSV treatment can provoke the activation of quiescent neural stem cells and prime their neurogenic capacity in the hippocampus via Wnt signaling in AD.
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Affiliation(s)
- Kumar Surya
- Department of Biochemistry, Molecular Neuro-gerontology Laboratory, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India
| | - Nivethitha Manickam
- Department of Animal Science, Laboratory of Stem Cells and Neuroregeneration, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India
| | - Kesavan Swaminathan Jayachandran
- Department of Bioinformatics, Molecular Cardiology and Drug Discovery Laboratory, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India
| | - Mahesh Kandasamy
- Department of Animal Science, Laboratory of Stem Cells and Neuroregeneration, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India
- University Grants Commission-Faculty Recharge Programme (UGC-FRP), New Delhi, India
| | - Muthuswamy Anusuyadevi
- Department of Biochemistry, Molecular Neuro-gerontology Laboratory, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India
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Nayak A, Warrier NM, Kumar P. Cancer Stem Cells and the Tumor Microenvironment: Targeting the Critical Crosstalk through Nanocarrier Systems. Stem Cell Rev Rep 2022; 18:2209-2233. [PMID: 35876959 PMCID: PMC9489588 DOI: 10.1007/s12015-022-10426-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/10/2022] [Indexed: 11/25/2022]
Abstract
The physiological state of the tumor microenvironment (TME) plays a central role in cancer development due to multiple universal features that transcend heterogeneity and niche specifications, like promoting cancer progression and metastasis. As a result of their preponderant involvement in tumor growth and maintenance through several microsystemic alterations, including hypoxia, oxidative stress, and acidosis, TMEs make for ideal targets in both diagnostic and therapeutic ventures. Correspondingly, methodologies to target TMEs have been investigated this past decade as stratagems of significant potential in the genre of focused cancer treatment. Within targeted oncotherapy, nanomedical derivates-nanocarriers (NCs) especially-have emerged to present notable prospects in enhancing targeting specificity. Yet, one major issue in the application of NCs in microenvironmental directed therapy is that TMEs are too broad a spectrum of targeting possibilities for these carriers to be effectively employed. However, cancer stem cells (CSCs) might portend a solution to the above conundrum: aside from being quite heavily invested in tumorigenesis and therapeutic resistance, CSCs also show self-renewal and fluid clonogenic properties that often define specific TME niches. Further scrutiny of the relationship between CSCs and TMEs also points towards mechanisms that underly tumoral characteristics of metastasis, malignancy, and even resistance. This review summarizes recent advances in NC-enabled targeting of CSCs for more holistic strikes against TMEs and discusses both the current challenges that hinder the clinical application of these strategies as well as the avenues that can further CSC-targeting initiatives. Central role of CSCs in regulation of cellular components within the TME.
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Affiliation(s)
- Aadya Nayak
- Department of Biotechnology, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Neerada Meenakshi Warrier
- Department of Biotechnology, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India
| | - Praveen Kumar
- Department of Biotechnology, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.
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Li C, Yoshimura T, Tian M, Wang Y, Kondo T, Yamamoto KI, Fujisawa M, Ohara T, Sakaguchi M, Matsukawa A. Exosomal Wnt7a from a low metastatic subclone promotes lung metastasis of a highly metastatic subclone in the murine 4t1 breast cancer. BREAST CANCER RESEARCH : BCR 2022; 24:60. [PMID: 36096830 PMCID: PMC9469633 DOI: 10.1186/s13058-022-01557-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 08/29/2022] [Indexed: 12/03/2022]
Abstract
Background Patients with triple-negative breast cancer (TNBC) often have poorer prognosis than those with other subtypes because of its aggressive behaviors. Cancer cells are heterogeneous, and only a few highly metastatic subclones metastasize. Although the majority of subclones may not metastasize, they could contribute by releasing factors that increase the capacity of highly metastatic cells and/or provide a favorable tumor microenvironment (TME). Here, we analyzed the interclonal communication in TNBC which leads to efficient cancer progression, particularly lung metastasis, using the polyclonal murine 4T1 BC model. Methods We isolated two 4T1 subclones, LM.4T1 and HM.4T1 cells with a low and a high metastatic potential, respectively, and examined the effects of LM.4T1 cells on the behaviors of HM.4T1 cells using the cell scratch assay, sphere-forming assay, sphere invasion assay, RT-qPCR, and western blotting in vitro. We also examined the contribution of LM.4T1 cells to the lung metastasis of HM.4T1 cells and TME in vivo. To identify a critical factor which may be responsible for the effects by LM.4T1 cells, we analyzed the data obtained from the GEO database. Results Co-injection of LM.4T1 cells significantly augmented lung metastases by HM.4T1 cells. LM.4T1-derived exosomes promoted the migration and invasion of HM.4T1 cells in vitro, and blocking the secretion of exosome abrogated their effects on HM.4T1 cells. Analyses of data obtained from the GEO database suggested that Wnt7a might be a critical factor responsible for the enhancing effects. In fact, a higher level of Wnt7a was detected in LM.4T1 cells, especially in exosomes, than in HM.4T1 cells, and deletion of Wnt7a in LM.4T1 cells significantly decreased the lung metastasis of HM.4T1 cells. Further, treatment with Wnt7a increased the spheroid formation by HM.4T1 cells via activation of the PI3K/Akt/mTOR signaling pathway. Finally, infiltration of αSMA-positive fibroblasts and angiogenesis was more prominent in tumors of LM.4T1 cells and deletion of Wnt7a in LM.4T1 cells markedly reduced angiogenesis. Conclusions We demonstrated, for the first time, that a low metastatic subclone can enhance lung metastasis of highly metastatic subclone via exosomal Wnt7a and propose Wnt7a as a molecular target to treat TNBC patients. Supplementary Information The online version contains supplementary material available at 10.1186/s13058-022-01557-5.
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Affiliation(s)
- Chunning Li
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama, 700-8558, Japan
| | - Teizo Yoshimura
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama, 700-8558, Japan.
| | - Miao Tian
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama, 700-8558, Japan.,Department of Cell Biology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama, 700-8558, Japan
| | - Yuze Wang
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama, 700-8558, Japan.,Department of Cell Biology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama, 700-8558, Japan
| | - Takamasa Kondo
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama, 700-8558, Japan.,Department of Cell Biology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama, 700-8558, Japan
| | - Ken-Ichi Yamamoto
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama, 700-8558, Japan.,Department of Cell Biology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama, 700-8558, Japan
| | - Masayoshi Fujisawa
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama, 700-8558, Japan.,Department of Cell Biology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama, 700-8558, Japan
| | - Toshiaki Ohara
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama, 700-8558, Japan.,Department of Cell Biology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama, 700-8558, Japan
| | - Masakiyo Sakaguchi
- Department of Cell Biology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama, 700-8558, Japan
| | - Akihiro Matsukawa
- Department of Pathology and Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata, Kita-ku, Okayama, 700-8558, Japan.
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Fan J, Reid RR, He TC. Pyrvinium doubles against WNT-driven cancer. J Biol Chem 2022; 298:102479. [PMID: 36096200 PMCID: PMC9525899 DOI: 10.1016/j.jbc.2022.102479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/07/2022] [Indexed: 11/29/2022] Open
Abstract
The WNT-β-catenin signaling pathway has a major role in regulating cell proliferation and differentiation. Aberrant activation of the pathway contributes to various human cancer types. Because casein kinase CK1α-initiated phosphorylation of β-catenin is a key first step to restrain WNT signaling, effective restoration of CK1α activity represents an innovative strategy to combat WNT-driven cancer. A recent study in JBC reveals the anthelmintic pyrvinium directly binds to CK1α as an activator and also stabilizes CK1α protein, doubling against WNT-driven cancer activity.
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Affiliation(s)
- Jiaming Fan
- Ministry of Education Key Laboratory of Diagnostic Medicine, and Department of Clinical Biochemistry, The School of Laboratory Medicine, Chongqing Medical University, Chongqing, China; Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois, USA.
| | - Russell R Reid
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois, USA; Laboratory of Craniofacial Suture Biology and Development, Department of Surgery Section of Plastic Surgery, The University of Chicago Medical Center, Chicago, Illinois, USA
| | - Tong-Chuan He
- Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, Illinois, USA.
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Shu C, Zheng X, Wuhafu A, Cicka D, Doyle S, Niu Q, Fan D, Qian K, Ivanov AA, Du Y, Mo X, Fu H. Acquisition of taxane resistance by p53 inactivation in ovarian cancer cells. Acta Pharmacol Sin 2022; 43:2419-2428. [PMID: 35031699 PMCID: PMC9433434 DOI: 10.1038/s41401-021-00847-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 12/20/2021] [Indexed: 12/22/2022]
Abstract
Ovarian cancer is one of the most common gynecologic malignancies in women and has a poor prognosis. Taxanes are a class of standard first-line chemotherapeutic agents for the treatment of ovarian cancer. However, tumor-intrinsic and acquired resistance to taxanes poses major challenges to improving clinical outcomes. Hence, there is an urgent clinical need to understand the mechanisms of resistance in order to discover potential biomarkers and therapeutic strategies to increase taxane sensitivity in ovarian cancer. Here, we report the identification of an association between the TP53 status and taxane sensitivity in ovarian cancer cells through complementary experimental and informatics approaches. We found that TP53 inactivation is associated with taxane resistance in ovarian cancer cells, supported by the evidence from (i) drug sensitivity profiling with bioinformatic analysis of large-scale cancer therapeutic response and genomic datasets and (ii) gene signature identification based on experimental isogenic cell line models. Further, our studies revealed TP53-dependent gene expression patterns, such as overexpression of ACSM3, as potential predictive biomarkers of taxane resistance in ovarian cancer. The TP53-dependent hyperactivation of the WNT/β-catenin pathway discovered herein revealed a potential vulnerability to exploit in developing combination therapeutic strategies. Identification of this genotype-phenotype relationship between the TP53 status and taxane sensitivity sheds light on TP53-directed patient stratification and therapeutic discoveries for ovarian cancer treatment.
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Affiliation(s)
- Changfa Shu
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
- Department of Gynecology and Obstetrics, The Third Xiangya Hospital of Central South University, Changsha, 410013, China
| | - Xi Zheng
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
- Cancer Institute, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310052, China
| | - Alafate Wuhafu
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
- The First Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Danielle Cicka
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Sean Doyle
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Qiankun Niu
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Dacheng Fan
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Kun Qian
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Andrey A Ivanov
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
- Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Yuhong Du
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
- Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Xiulei Mo
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Haian Fu
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
- Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, GA, 30322, USA.
- Department of Hematology and Medical Oncology and Winship Cancer Institute, Emory University, Atlanta, GA, 30322, USA.
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Human Umbilical Cord Mesenchymal Stem Cell-Derived Conditioned Medium Promotes Human Endometrial Cell Proliferation through Wnt/β-Catenin Signaling. BIOMED RESEARCH INTERNATIONAL 2022; 2022:8796093. [PMID: 36082157 PMCID: PMC9448603 DOI: 10.1155/2022/8796093] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 05/08/2022] [Accepted: 07/12/2022] [Indexed: 11/30/2022]
Abstract
Purpose Mesenchymal stem cells (MSCs) and their derivant are among the promising treatments for intrauterine adhesion (IUA); they have been reported to repair the endometrial injury by proliferating endometrial cells. However, the signal pathways involved are not clear. This study investigated the role of human umbilical cord mesenchymal stem cell-derived conditioned medium (hUCMSC-CM) in relieving IUA to find out whether Wnt/β-catenin signaling was involved, and if so, to determine the possible ligands. Methods After endometrial epithelial cells (EECs) were treated with hUCMSC-CM, their proliferation and migration were measured by the CCK8 assay and the scratch assay. The activation of Wnt/β-catenin signaling was measured by Western blots, fluorescent staining, and T-cell factor/lymphoid enhancer factor (TCF/LEF) luciferase. A Wnt inhibitor (XAV393) was used to inhibit the proliferation effect of hUCMSC-CM in EECs. Wnt5a expression in hUCMSC was measured by Western blots and fluorescent staining, and Wnt5a in hUCMSC-CM was detected by enzyme-linked immunosorbent assay (ELISA), to further clarify the mechanism. Results As shown by the CCK8 assay, hUCMSC-CM promoted proliferation and migration of EECs. The expression of β-catenin, c-myc, and cyclin D1 increased in EECs after being treated with hUCMSC-CM. Moreover, hUCMSC-CM was found to promote β-catenin delivery into nuclei by Western blot and fluorescent staining; meanwhile, the inhibitor (XAV393) could restrain this process and inhibit the effect of hUCMSC-CM on EEC proliferation. Wnt5a was detected in hUCMSCs and hUCMSC-CM, which might be a potential therapeutic target. Conclusion This study demonstrated that hUCMSC-CM promoted human endometrial cell proliferation through Wnt/β-catenin signaling, and Wnt5a might be a potential activator. This would be one of the activating signal pathways in the MSC-related treatment of IUA.
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Melcher C, Yu J, Duong VHH, Westphal K, Helmi Siasi Farimany N, Shaverskyi A, Zhao B, Strowig T, Glage S, Brand K, Chan AC, Föger N, Lee KH. B cell-mediated regulatory mechanisms control tumor-promoting intestinal inflammation. Cell Rep 2022; 40:111051. [PMID: 35830810 DOI: 10.1016/j.celrep.2022.111051] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 04/28/2022] [Accepted: 06/14/2022] [Indexed: 11/03/2022] Open
Abstract
Mechanisms underlying tumor-promoting inflammatory processes in colitis-associated colorectal cancer (CAC) remain largely elusive. Here, we provide genetic evidence for distinct B cell-mediated immunoregulatory mechanisms that protect from chronic colitis versus CAC. We demonstrate an inherent capacity of interleukin-10 (IL-10)-producing B cells to differentiate into immunoglobulin A (IgA) plasma cells (PCs) upon Toll-like receptor (TLR) activation. Our data show that B cell-derived IL-10 is essential to limit pathogenic T helper type 1 (Th1)/Th17 T cell responses during chronic colitis, while IgA PCs derived from IL-10+ B cells are being implicated in restraining tumorigenesis during CAC. Formation of a tumor-protective intestinal environment was associated with clonal expansion of specific types of colonic IgA PCs and development of an altered microbiota that attenuated CAC. We thus propose that regulatory B cell-mediated immunomodulation entails temporal release of IL-10, which is superseded by the generation of specific IgA affecting the microbial community, thereby controlling chronic inflammation and tumorigenesis in a distinctive but interrelated manner.
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Affiliation(s)
- Christian Melcher
- Inflammation Research Group, Hannover Medical School, 30625 Hannover, Germany; Institute of Clinical Chemistry, Hannover Medical School, 30625 Hannover, Germany
| | - Jinbo Yu
- Inflammation Research Group, Hannover Medical School, 30625 Hannover, Germany; Institute of Clinical Chemistry, Hannover Medical School, 30625 Hannover, Germany
| | - Vu Huy Hoang Duong
- Inflammation Research Group, Hannover Medical School, 30625 Hannover, Germany; Institute of Clinical Chemistry, Hannover Medical School, 30625 Hannover, Germany
| | - Katrin Westphal
- Inflammation Research Group, Hannover Medical School, 30625 Hannover, Germany; Institute of Clinical Chemistry, Hannover Medical School, 30625 Hannover, Germany
| | - Noushin Helmi Siasi Farimany
- Inflammation Research Group, Hannover Medical School, 30625 Hannover, Germany; Institute of Clinical Chemistry, Hannover Medical School, 30625 Hannover, Germany
| | - Anton Shaverskyi
- Inflammation Research Group, Hannover Medical School, 30625 Hannover, Germany; Institute of Clinical Chemistry, Hannover Medical School, 30625 Hannover, Germany
| | - Bei Zhao
- Department of Microbial Immune Regulation, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany; Hannover Medical School, 30625 Hannover, Germany
| | - Till Strowig
- Department of Microbial Immune Regulation, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany; Hannover Medical School, 30625 Hannover, Germany
| | - Silke Glage
- Experimental Pathology, Institute for Laboratory Animal Science, Hannover Medical School, 30625 Hannover, Germany
| | - Korbinian Brand
- Institute of Clinical Chemistry, Hannover Medical School, 30625 Hannover, Germany
| | - Andrew C Chan
- Research, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA
| | - Niko Föger
- Inflammation Research Group, Hannover Medical School, 30625 Hannover, Germany; Institute of Clinical Chemistry, Hannover Medical School, 30625 Hannover, Germany
| | - Kyeong-Hee Lee
- Inflammation Research Group, Hannover Medical School, 30625 Hannover, Germany; Institute of Clinical Chemistry, Hannover Medical School, 30625 Hannover, Germany.
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Guo K, Duan J, Lu J, Xiao L, Han L, Zeng S, Tang X, Li W, Huang L, Zhang Y. TNF-α-inducing protein of Helicobacter pylori promotes EMT and cancer stem-like cells properties via activation of Wnt/β-catenin signaling pathway in gastric cancer cells. Pathog Dis 2022; 80:6626024. [PMID: 35776950 DOI: 10.1093/femspd/ftac025] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 06/20/2022] [Accepted: 06/28/2022] [Indexed: 11/13/2022] Open
Abstract
Tumor necrosis factor-α-inducing protein (Tipα) is a newly identified toxin, which promotes the inflammation and carcinogenesis caused by Helicobacter pylori (H. pylori). However, its mechanism of pathogenesis is still unclear. To investigate the carcinogenic mechanisms of Tipα, SGC7901 cells and SGC7901-derived cancer stem-like cells (CSCs) were stimulated by recombinant Tipα protein with or without Wnt/β-catenin signaling inhibitor XAV939. qRT-PCR and Western blotting were employed to detect expression of epithelial-mesenchymal transition (EMT), CSCs markers, and downstream target genes of this signaling pathway. The cell migration ability was measured by wound healing assay and transwell assay. Our results indicated that Tipα promoted CSC properties of SGC7901 spheroids, including increased expression of CSC specific surface markers CD44, Oct4, Nanog, and an increased capacity for self-renewal. Tipα activated Wnt/β-catenin signaling in both SGC7901 cells or CSCs. Furthermore, Tipα induced the EMT and increased the expressions of downstream target genes of this signaling, including c-myc, cyclin D1, and CD44. However, XAV939 pretreatment inhibited Tipα-induced EMT and CSC properties in SGC7901 cells or CSCs. These results suggest that Tipα promotes EMT and CSC-like properties in gastric cancer cells through activation of Wnt/β-catenin signaling pathway, thereby accelerating the progression of gastric cancer.
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Affiliation(s)
- Kaiyun Guo
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China; Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control; Hunan Province Innovative Training Base for Postgraduates, University of South China and Nanyue Biopharmaceutical Co. Ltd., Hengyang 421001, Hunan, China
| | - Jie Duan
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China; Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control; Hunan Province Innovative Training Base for Postgraduates, University of South China and Nanyue Biopharmaceutical Co. Ltd., Hengyang 421001, Hunan, China
| | - Jingwen Lu
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China; Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control; Hunan Province Innovative Training Base for Postgraduates, University of South China and Nanyue Biopharmaceutical Co. Ltd., Hengyang 421001, Hunan, China
| | - Lingqiao Xiao
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China; Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control; Hunan Province Innovative Training Base for Postgraduates, University of South China and Nanyue Biopharmaceutical Co. Ltd., Hengyang 421001, Hunan, China
| | - Liang Han
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China; Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control; Hunan Province Innovative Training Base for Postgraduates, University of South China and Nanyue Biopharmaceutical Co. Ltd., Hengyang 421001, Hunan, China
| | - Shasha Zeng
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China; Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control; Hunan Province Innovative Training Base for Postgraduates, University of South China and Nanyue Biopharmaceutical Co. Ltd., Hengyang 421001, Hunan, China
| | - Xin Tang
- School of Nursing, University of South China, Hengyang 421001, Hunan, China
| | - Wenjing Li
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China; Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control; Hunan Province Innovative Training Base for Postgraduates, University of South China and Nanyue Biopharmaceutical Co. Ltd., Hengyang 421001, Hunan, China
| | - Lijun Huang
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China; Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control; Hunan Province Innovative Training Base for Postgraduates, University of South China and Nanyue Biopharmaceutical Co. Ltd., Hengyang 421001, Hunan, China
| | - Yan Zhang
- Institute of Pathogenic Biology, Hengyang Medical College, University of South China; Hunan Provincial Key Laboratory for Special Pathogens Prevention and Control; Hunan Province Innovative Training Base for Postgraduates, University of South China and Nanyue Biopharmaceutical Co. Ltd., Hengyang 421001, Hunan, China
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Jing Z, Liang Z, Yang L, Du W, Yu T, Tang H, Li C, Wei W. Bone formation and bone repair: The roles and crosstalk of osteoinductive signaling pathways. Process Biochem 2022. [DOI: 10.1016/j.procbio.2022.04.033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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40
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Karami Fath M, Azargoonjahromi A, Kiani A, Jalalifar F, Osati P, Akbari Oryani M, Shakeri F, Nasirzadeh F, Khalesi B, Nabi-Afjadi M, Zalpoor H, Mard-Soltani M, Payandeh Z. The role of epigenetic modifications in drug resistance and treatment of breast cancer. Cell Mol Biol Lett 2022; 27:52. [PMID: 35764927 PMCID: PMC9238060 DOI: 10.1186/s11658-022-00344-6] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 05/24/2022] [Indexed: 02/08/2023] Open
Abstract
Background Breast cancer is defined as a biological and molecular heterogeneous disorder that originates from breast cells. Genetic predisposition is the most important factor giving rise to this malignancy. The most notable mutations in breast cancer occur in the BRCA1 and BRCA2 genes. Owing to disease heterogeneity, lack of therapeutic target, anti-cancer drug resistance, residual disease, and recurrence, researchers are faced with challenges in developing strategies to treat patients with breast cancer. Results It has recently been reported that epigenetic processes such as DNA methylation and histone modification, as well as microRNAs (miRNAs), have potently contributed to the pathophysiology, diagnosis, and treatment of breast cancer. These observations have persuaded researchers to move their therapeutic approaches beyond the genetic framework toward the epigenetic concept. Conclusion Herein we discuss the molecular and epigenetic mechanisms underlying breast cancer progression and resistance as well as various aspects of epigenetic-based therapies as monotherapy and combined with immunotherapy.
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Affiliation(s)
- Mohsen Karami Fath
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | | | - Arash Kiani
- Student Research Committee, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Fateme Jalalifar
- School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Parisa Osati
- Chemical Engineering Department, Fouman Faculty of Engineering, College of Engineering, University of Tehran, Fouman, Iran
| | - Mahsa Akbari Oryani
- Department of Pathology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fateh Shakeri
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Farhad Nasirzadeh
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Behman Khalesi
- Department of Research and Production of Poultry Viral Vaccine, Razi Vaccine and Serum Research Institute, Agricultural Research Education and Extension Organization, Karaj, Iran
| | - Mohsen Nabi-Afjadi
- Department of Biochemistry, Faculty of Biological Science, Tarbiat Modares University, Tehran, Iran
| | - Hamidreza Zalpoor
- Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Maysam Mard-Soltani
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Dezful University of Medical Sciences, Dezful, Iran.
| | - Zahra Payandeh
- Department Medical Biochemistry and Biophysics, Division Medical Inflammation Research, Karolinska Institute, Stockholm, Sweden.
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41
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The glycoprotein Wnt6 regulates human dental papilla cells differentiation by canonical Wnt signaling pathway. Arch Oral Biol 2022; 141:105469. [DOI: 10.1016/j.archoralbio.2022.105469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 05/30/2022] [Accepted: 05/31/2022] [Indexed: 11/17/2022]
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Adiga D, Bhat S, Chakrabarty S, Kabekkodu SP. DOC2B is a negative regulator of Wnt/β-catenin signaling pathway in cervical cancer. Pharmacol Res 2022; 180:106239. [PMID: 35500882 DOI: 10.1016/j.phrs.2022.106239] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 04/13/2022] [Accepted: 04/27/2022] [Indexed: 10/18/2022]
Abstract
DOC2B is a ubiquitously expressed isoform of the double C-2 protein family that requires Ca2+ for most of its physiological functions. Initial findings have indicated that DOC2B participates in exocytosis, vesicular transport, insulin secretion and regulation, glucose homeostasis, and neurotransmitter release. Aberrant expression of DOC2B has been reported in diabetes, leukemia, and cervical cancer (CC). Our earlier studies have demonstrated the inhibitory effects of DOC2B on CC cell proliferation, migration, invasion, and EMT and suggested the possible role of DOC2B in Wnt signaling inhibition. However, the association between DOC2B downregulation and Wnt/β-catenin signaling activation and the underlying molecular mechanism remain elusive. Herein, we found that DOC2B inhibited Wnt/β-catenin pathway by enhancing the expression of the components of the CTNNB1 destruction complex and by fostering proteasomal degradation of CTNNB1. The translocation of CTNNB1 to the nucleus and its interaction with TCF/LEF family transcription factors was perturbed in the presence of DOC2B in a GSK3β independent manner. Further, we have identified DKK1 as one of the upregulated genes in the presence of DOC2B. DKK1 inhibition in DOC2B expressing cells by WAY262611 reactivated Wnt/β-catenin signaling, relieved DOC2B induced senescence, and alleviated the inhibitory effects of DOC2B on the aforementioned malignant behaviors. We have provided evidence for DOC2B-DKK1-senescence-Wnt/β-catenin-EMT signaling crosstalk to have tumor growth regulatory functions in CC. Thus, targeting DOC2B-DKK1-senescence-Wnt/β-catenin-EMT signaling crosstalk via activation of DOC2B may offer a novel approach to restraint malignant behaviors in CC.
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Affiliation(s)
- Divya Adiga
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, India
| | - Samatha Bhat
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, India
| | - Sanjiban Chakrabarty
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, India
| | - Shama Prasada Kabekkodu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, India.
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Huang J, Zhou Y, Xiao W, Deng P, Wei Q, Lu W. Serum β-catenin changes vary among different stages of osteonecrosis of the femoral head: an exploratory biomarker study. BMC Musculoskelet Disord 2022; 23:434. [PMID: 35538460 PMCID: PMC9088107 DOI: 10.1186/s12891-022-05399-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Accepted: 05/05/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Wnt/β-catenin signaling pathway is closely related to the pathogenesis Osteonecrosis of the femoral head (ONFH). β-catenin, as a major component of Wnt signaling pathway, plays a vital role in the proliferation of osteoblasts. But the effect of altering β-catenin level on the early diagnosis and staging of ONFH has not been studied. Our purpose is to investigate the role of β-catenin level in the progress of ONFH. METHOD One hundred and one patients with three stages of ONFH and fifty healthy controls were recruited between May 2016 and November 2016. We divided the patients into 32 cases of stage II, 41 cases of stage III and 28 cases of stage IV according to the Association Research Circulation Osseous (ARCO) classification. We evaluated the clinical bone histomorphology, expression position and level of β-catenin as well as the plasma β-catenin level. We investigated the level of β-catenin from the serum and tissue samples using ELISA and Western Blot assay. We also evaluated the expression of β-catenin in bone tissue by immunohistochemistry. Data were analyzed by independent t-test and ANOVA. RESULTS We found that the mean (± SD) serum level of β-catenin was 66.99 ± 3.032 ng/ml in the ONFH patients, which was higher than 20.14 ± 1.715 ng/ml observed in the control group (P < 0.001). Moreover, the β-catenin levels were 49.30 ± 4.649 ng/ml, 72.54 ± 4.864 ng/ml and 79.10 ± 4.773 ng/ml in the ONFH patients with ARCO stage II, stage III and stage IV respectively, showing significant difference among them (P < 0.001). We also found that the area under the curve (AUC) calculated by ROC curve analysis to determine the values for β-catenin levels in ONFH compared with those in the control group was 0.9358 (P < 0.001), where the sensitivity was 77.23% and specificity was 98.00%. CONCLUSION Our results indicate that the increased β-catenin may play a vital role in the progress of ONFH and the level of β-catenin is correlated with ARCO stages. The cut-off concentration may be used as one of the sensitive marks to assess the disease process of ONFH.
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Affiliation(s)
- Junyuan Huang
- First Affiliated Hospital of Guangzhou University of Chinese Medicine, No. 16, Airport Road, Baiyun District, Guangzhou City, 510405, China
| | - Yingchun Zhou
- First Affiliated Hospital of Guangzhou University of Chinese Medicine, No. 16, Airport Road, Baiyun District, Guangzhou City, 510405, China
| | - Wei Xiao
- Department of Pathogen Biology, Shenzhen University School of Medicine, Shenzhen, China
| | - Peng Deng
- First Affiliated Hospital of Guangzhou University of Chinese Medicine, No. 16, Airport Road, Baiyun District, Guangzhou City, 510405, China
| | - Qiushi Wei
- Guangdong Research Institute for Orthopedics and Traumatology of Chinese Medicine, No. 16, Airport Road, Baiyun District, Guangzhou City, 510405, China. .,Joint Center, The Third Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
| | - Weiguo Lu
- First Affiliated Hospital of Guangzhou University of Chinese Medicine, No. 16, Airport Road, Baiyun District, Guangzhou City, 510405, China.
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Huang Z, Gao H, Qing L, Wang B, He C, Luo N, Lu C, Fan S, Gu P, Zhao H. A long noncoding RNA GTF2IRD2P1 suppresses cell proliferation in bladder cancer by inhibiting the Wnt/β‑catenin signaling pathway. PeerJ 2022; 10:e13220. [PMID: 35433119 PMCID: PMC9009331 DOI: 10.7717/peerj.13220] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 03/14/2022] [Indexed: 01/12/2023] Open
Abstract
Background There is growing evidence that long non-coding RNAs (LncRNAs) are key in the development of a variety of human tumors. However, the role of lncRNA GTF2IRD2P1 has not been well studied in cancer. The impact of GTF2IRD2P1 on the biological function and clinical relevance in bladder cancer is largely unknown. This study aimed to investigate the biological role of GTF2IRD2P1 in bladder evolution and carcinogenesis. Methods We used bioinformatics to obtain the lncRNA GTF2IRD2P1 from bladder urothelial carcinoma (BLCA) in The Cancer Genome Atlas (TCGA) database. The expression of lncRNA GTF2IRD2P1 was detected by qRT-PCR. The CCK8 assay and flow cytometry were used to detect the lncRNA GTF2IRD2P1 function on the proliferation of bladder cancer cells. A western blot was used to calculate the protein level of cell cycle proteins and Wnt signaling pathway proteins. The effect of lncRNA GTF2IRD2P1 on tumorigenesis of bladder cancer was confirmed by a xenograft nude mouse model. Results GTF2IRD2P1 expression was found to be lower in both human bladder cancer tissues and cell lines (UM-UC-3, RT4, and 5637), and elevated in T24 compared to the corresponding normal controls. GTF2IRD2P1 expression was also enhanced after transfection of UM-UC-3 cells with the overexpression vector. Meanwhile, overexpression of GTF2IRD2P1 inhibited the proliferation of UM-UC-3 and prolonged the cell cycle. The silencing of GTF2IRD2P1 significantly increased the proliferation and shortened the cell cycle of T24 cells and induced Wnt signaling activity to promote the progression of bladder cancer. Similarly, the transplanted tumor nude mouse model demonstrated that silencing GTF2IRD2P1 strengthens the progression of bladder cancer by targeting the Wnt signaling pathway.
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Affiliation(s)
- Zhuo Huang
- Department of Urology, First Affiliated Hospital of Kunming Medical University, Kunming Medical College, Kunming, Yunnan, People’s Republic of China
| | - Hongbin Gao
- Department of Urology, First Affiliated Hospital of Kunming Medical University, Kunming Medical College, Kunming, Yunnan, People’s Republic of China,Clinical Research Center for Chronic Kidney Disease, First Affiliated Hospital of Kunming Medical University, Kunming Medical College, Kunming, Yunnan, People’s Republic of China
| | - Liangliang Qing
- Department of Urology, First Affiliated Hospital of Kunming Medical University, Kunming Medical College, Kunming, Yunnan, People’s Republic of China
| | - Biao Wang
- Department of Urology, First Affiliated Hospital of Kunming Medical University, Kunming Medical College, Kunming, Yunnan, People’s Republic of China
| | - Chaoyong He
- Department of Urology, First Affiliated Hospital of Kunming Medical University, Kunming Medical College, Kunming, Yunnan, People’s Republic of China
| | - Ning Luo
- Department of Urology, First Affiliated Hospital of Kunming Medical University, Kunming Medical College, Kunming, Yunnan, People’s Republic of China
| | - Chuncheng Lu
- Department of Urology, First Affiliated Hospital of Kunming Medical University, Kunming Medical College, Kunming, Yunnan, People’s Republic of China
| | - Shipeng Fan
- Department of Urology, First Affiliated Hospital of Kunming Medical University, Kunming Medical College, Kunming, Yunnan, People’s Republic of China
| | - Peng Gu
- Department of Urology, First Affiliated Hospital of Kunming Medical University, Kunming Medical College, Kunming, Yunnan, People’s Republic of China,Clinical Research Center for Chronic Kidney Disease, First Affiliated Hospital of Kunming Medical University, Kunming Medical College, Kunming, Yunnan, People’s Republic of China
| | - Hui Zhao
- Department of Urology, First Affiliated Hospital of Kunming Medical University, Kunming Medical College, Kunming, Yunnan, People’s Republic of China,Clinical Research Center for Chronic Kidney Disease, First Affiliated Hospital of Kunming Medical University, Kunming Medical College, Kunming, Yunnan, People’s Republic of China
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Liang W, Huang L, Ma X, Dong L, Cheng R, Dehdarani M, Karamichos D, Ma JX. Pathogenic Role of Diabetes-Induced Overexpression of Kallistatin in Corneal Wound Healing Deficiency Through Inhibition of Canonical Wnt Signaling. Diabetes 2022; 71:747-761. [PMID: 35044447 PMCID: PMC8965664 DOI: 10.2337/db21-0740] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 12/27/2021] [Indexed: 01/21/2023]
Abstract
It was reported previously that circulation levels of kallistatin, an endogenous Wnt signaling inhibitor, are increased in patients with diabetes. The current study was conducted to determine the role of kallistatin in delayed wound healing in diabetic corneas. Immunostaining and Western blot analysis showed kallistatin levels were upregulated in corneas from humans and rodents with diabetes. In murine corneal wound healing models, the canonical Wnt signaling was activated in nondiabetic corneas and suppressed in diabetic corneas, correlating with delayed wound healing. Transgenic expression of kallistatin suppressed the activation of Wnt signaling in the cornea and delayed wound healing. Local inhibition of Wnt signaling in the cornea by kallistatin, an LRP6-blocking antibody, or the soluble VLDL receptor ectodomain (an endogenous Wnt signaling inhibitor) delayed wound healing. In contrast, ablation of the VLDL receptor resulted in overactivation of Wnt/β-catenin signaling and accelerated corneal wound healing. Activation of Wnt signaling in the cornea accelerated wound healing. Activation of Wnt signaling promoted human corneal epithelial cell migration and proliferation, which was attenuated by kallistatin. Our findings suggested that diabetes-induced overexpression of kallistatin contributes to delayed corneal wound healing by inhibiting the canonical Wnt signaling. Thus, kallistatin and Wnt/β-catenin signaling in the cornea could be potential therapeutic targets for diabetic corneal complications.
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Affiliation(s)
- Wentao Liang
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Li Huang
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
- Department of Ophthalmology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Xiang Ma
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Lijie Dong
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
- Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, China
| | - Rui Cheng
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Marcus Dehdarani
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Dimitrios Karamichos
- North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX
- Department of Pharmaceutical Sciences, University of North Texas Health Science Center, Fort Worth, TX
- Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX
| | - Jian-xing Ma
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
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Zhang Y, Wang H, Tu W, Abbas Raza SH, Cao J, Huang J, Wu H, Fan C, Wang S, Zhao Y, Tan Y. Comparative Transcriptome Analysis Provides Insight into Spatio-Temporal Expression Characteristics and Genetic Regulatory Network in Postnatal Developing Subcutaneous and Visceral Fat of Bama Pig. Front Genet 2022; 13:844833. [PMID: 35432468 PMCID: PMC9008487 DOI: 10.3389/fgene.2022.844833] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 03/04/2022] [Indexed: 12/23/2022] Open
Abstract
The depot differences between Subcutaneous Fat (SAF) and Visceral Fat (VAF) are critical for human well-being and disease processes in regard to energy metabolism and endocrine function. Miniature pigs (Sus scrofa) are ideal biomedical models for human energy metabolism and obesity due to the similarity of their lipid metabolism with that of humans. However, the regulation of differences in fat deposition and development remains unclear. In this study, the development of SAF and VAF was characterized and compared in Bama pig during postnatal development (infancy, puberty and adulthood), using RNA sequencing techniques (RNA-Seq). The transcriptome of SAF and VAF was profiled and isolated from 1-, 3- and 6 months-old pigs and identified 23,636 expressed genes, of which 1,165 genes were differentially expressed between the depots and/or developmental stages. Upregulated genes in SAF showed significant function and pathway enrichment in the central nervous system development, lipid metabolism, oxidation-reduction process and cell adhesion, whereas genes involved in the immune system, actin cytoskeleton organization, male gonad development and the hippo signaling pathway were preferentially expressed in VAF. Miner analysis of short time-series expression demonstrated that differentiation in gene expression patterns between the two depots corresponded to their distinct responses in sexual development, hormone signaling pathways, lipid metabolism and the hippo signaling pathway. Transcriptome analysis of SAF and VAF suggested that the depot differences in adipose tissue are not only related to lipid metabolism and endocrine function, but are closely associated with sexual development and organ size regulation.
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Affiliation(s)
- Yingying Zhang
- Institute of Animal Husbandry and Veterinary Science, Shanghai Academy of Agricultural Sciences, Shanghai, China
- Shanghai Engineering Research Center of Breeding Pig, Shanghai, China
- *Correspondence: Yingying Zhang, ; Yongsong Tan,
| | - Hongyang Wang
- Institute of Animal Husbandry and Veterinary Science, Shanghai Academy of Agricultural Sciences, Shanghai, China
- Shanghai Engineering Research Center of Breeding Pig, Shanghai, China
| | - Weilong Tu
- Institute of Animal Husbandry and Veterinary Science, Shanghai Academy of Agricultural Sciences, Shanghai, China
- Shanghai Engineering Research Center of Breeding Pig, Shanghai, China
| | | | - Jianguo Cao
- Institute of Animal Husbandry and Veterinary Science, Shanghai Academy of Agricultural Sciences, Shanghai, China
- Shanghai Engineering Research Center of Breeding Pig, Shanghai, China
| | - Ji Huang
- Institute of Animal Husbandry and Veterinary Science, Shanghai Academy of Agricultural Sciences, Shanghai, China
- Shanghai Engineering Research Center of Breeding Pig, Shanghai, China
| | - Huali Wu
- Institute of Animal Husbandry and Veterinary Science, Shanghai Academy of Agricultural Sciences, Shanghai, China
- Shanghai Engineering Research Center of Breeding Pig, Shanghai, China
| | - Chun Fan
- Shanghai Laboratory Animal Research Center, Shanghai, China
| | | | - Ying Zhao
- Shanghai Laboratory Animal Research Center, Shanghai, China
| | - Yongsong Tan
- Institute of Animal Husbandry and Veterinary Science, Shanghai Academy of Agricultural Sciences, Shanghai, China
- Shanghai Engineering Research Center of Breeding Pig, Shanghai, China
- *Correspondence: Yingying Zhang, ; Yongsong Tan,
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Abd El Salam ASG, Samra YA, El-Shishtawy MM. Cinnamaldehyde Relieves Induced Hepatocellular Carcinoma in Rat Model via Targeting Wnt/β-Catenin Pathway. Sci Pharm 2022; 90:22. [DOI: 10.3390/scipharm90020022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/10/2022] Open
Abstract
Cinnamaldehyde (CA) is a natural compound that has promising biological activity. The current study investigates the antitumor activity of CA in thioacetamide induced hepatocellular carcinoma (HCC) in rats through targeting the Wnt/β-catenin pathway and evaluates the capability of CA to relieve hepatocytes oxidative stress in the HCC-rat model. After 16 weeks of HCC induction by thioacetamide (TAA), rats were treated for 7 consecutive weeks with CA daily; i.p. injection, Alpha-fetoprotein (AFP) level, necroinflammatory score and fibrosis percentage were measured to assess HCC development. The Wnt/β-catenin pathway was evaluated by measuring the hepatic protein level of Wnt-3a, β-catenin, cyclin D, matrix metalloproteinase-9 (MMP-9), and vascular endothelial growth factor (VEGF). Furthermore, hepatocytes’ oxidative stress was assessed by measuring hepatic GSH and MDA contents. Results showed that CA was significantly inhibiting the Wnt/β-catenin pathway through the downregulation of hepatic Wnt-3a, β-catenin, cyclin D, MMP-9, and VEGF. Moreover, CA ameliorates hepatocytes’ oxidative stress via lowering hepatic MDA content and rising hepatic GSH content. Thus, in conclusion, CA is a promising treatment for HCC. It not only has an effective antitumor activity but also ameliorates hepatocytes’ oxidative stress.
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Affiliation(s)
| | - Yara A. Samra
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
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Hsieh HL, Yu MC, Cheng LC, Yeh TS, Tsai MM. Molecular mechanism of therapeutic approaches for human gastric cancer stem cells. World J Stem Cells 2022; 14:76-91. [PMID: 35126829 PMCID: PMC8788185 DOI: 10.4252/wjsc.v14.i1.76] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 05/15/2021] [Accepted: 12/21/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is a primary cause of cancer-related mortality worldwide, and even after therapeutic gastrectomy, survival rates remain poor. The presence of gastric cancer stem cells (GCSCs) is thought to be the major reason for resistance to anticancer treatment (chemotherapy or radiotherapy), and for the development of tumor recurrence, epithelial-mesenchymal transition, and metastases. Additionally, GCSCs have the capacity for self-renewal, differentiation, and tumor initiation. They also synthesize antiapoptotic factors, demonstrate higher performance of drug efflux pumps, and display cell plasticity abilities. Moreover, the tumor microenvironment (TME; tumor niche) that surrounds GCSCs contains secreted growth factors and supports angiogenesis and is thus responsible for the maintenance of the growing tumor. However, the genesis of GCSCs is unclear and exploration of the source of GCSCs is essential. In this review, we provide up-to-date information about GCSC-surface/intracellular markers and GCSC-mediated pathways and their role in tumor development. This information will support improved diagnosis, novel therapeutic approaches, and better prognosis using GCSC-targeting agents as a potentially effective treatment choice following surgical resection or in combination with chemotherapy and radiotherapy. To date, most anti-GCSC blockers when used alone have been reported as unsatisfactory anticancer agents. However, when used in combination with adjuvant therapy, treatment can improve. By providing insights into the molecular mechanisms of GCSCs associated with tumors in GC, the aim is to optimize anti-GCSCs molecular approaches for GC therapy in combination with chemotherapy, radiotherapy, or other adjuvant treatment.
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Affiliation(s)
- Hsi-Lung Hsieh
- Department of Nursing, Division of Basic Medical Sciences, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan
- Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan
- Department of Neurology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Ming-Chin Yu
- Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Department of General Surgery, New Taipei Municipal TuCheng Hospital, New Taipei 236, Taiwan
| | - Li-Ching Cheng
- Department of Nursing, Division of Basic Medical Sciences, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan
| | - Ta-Sen Yeh
- Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Ming-Ming Tsai
- Department of Nursing, Division of Basic Medical Sciences, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan
- Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan
- Department of General Surgery, Chang Gung Memorial Hospital, Chiayi 613, Taiwan.
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Xu W, Li Y, Feng R, He P, Zhang Y. γ-Tocotrienol induced the proliferation and differentiation of MC3T3-E1 cells through the stimulation of the Wnt/β-catenin signaling pathway. Food Funct 2022; 13:398-410. [PMID: 34908071 DOI: 10.1039/d1fo02583j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
γ-Tocotrienol (γ-T3), an isoprenoid phytochemical, has shown the promotion of osteoblast proliferation and differentiation in our previous study. In this study, its underlying mechanism was investigated through regulating the Wnt/β-catenin signaling pathway in MC3T3-E1 cells. Comparative experiment results showed that γ-T3, not α-tocopherol (α-TOC) increased more significantly the viability and differentiation in MC3T3-E1 cells. After that, the cells were incubated with 10 mM LiCl, or 4 μM γ-T3 with or without 1 μM XAV-939. γ-T3 at 4 μM stimulated the Wnt/β-catenin signaling pathway by increasing the expression and nuclear accumulation of β-catenin, and the expressions of their downstream factors, such as cyclin-D1, c-Myc, BMP2 and BMP-4 in MC3T3-E1 cells. γ-T3 not only upregulated the viability, induced G0/G1 to the S phase, and promoted the expressions of PCNA (Proliferating Cell Nuclear Antigen) and Ki-67, but also increased ALP activity and the expressions of ON, OPN and OCN. Moreover, the effects of γ-T3 on the MC3T3-E1 cells resembled the actions of LiCl, an activator of the Wnt/β-catenin signaling pathway. Notably, all these effects of γ-T3 on the MC3T3-E1 cells were completely blocked by the Wnt/β-catenin signaling pathway inhibitor XAV-939. Our data demonstrated that γ-T3 can target β-catenin to enhance the Wnt/β-catenin signaling pathway, which led to increased expressions of the downstream cell proliferation and cell cycle-associated (cyclin D1 and c-myc), and cell differentiation-associated (BMP-2 and BMP-4) target genes, and ultimately promoted MC3T3-E1 cell proliferation and differentiation. Therefore, γ-T3 may be a potential agent to prevent and reverse osteoporosis due to its safety and powerful abilities of osteogenesis.
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Affiliation(s)
- Weili Xu
- Innovation Research Center for Special Food-Medicine and Biochemical Engineering, School of Chemistry and Chemical Engineering, Harbin Institute of Technology, 92 Xidazhi Street, Nangang District, Harbin, China.
| | - Yutong Li
- Innovation Research Center for Special Food-Medicine and Biochemical Engineering, School of Chemistry and Chemical Engineering, Harbin Institute of Technology, 92 Xidazhi Street, Nangang District, Harbin, China.
| | - Rennan Feng
- Department of Nutrition and Food Hygiene, Public Health College, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, China
| | - Pan He
- Innovation Research Center for Special Food-Medicine and Biochemical Engineering, School of Chemistry and Chemical Engineering, Harbin Institute of Technology, 92 Xidazhi Street, Nangang District, Harbin, China.
| | - Yuqi Zhang
- Innovation Research Center for Special Food-Medicine and Biochemical Engineering, School of Chemistry and Chemical Engineering, Harbin Institute of Technology, 92 Xidazhi Street, Nangang District, Harbin, China.
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50
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Jiménez-Guerrero R, Belmonte-Fernández A, Flores ML, González-Moreno M, Pérez-Valderrama B, Romero F, Japón MÁ, Sáez C. Wnt/β-Catenin Signaling Contributes to Paclitaxel Resistance in Bladder Cancer Cells with Cancer Stem Cell-Like Properties. Int J Mol Sci 2021; 23:ijms23010450. [PMID: 35008872 PMCID: PMC8745426 DOI: 10.3390/ijms23010450] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/20/2021] [Accepted: 12/29/2021] [Indexed: 12/14/2022] Open
Abstract
The Wnt/β-catenin pathway plays an important role in tumor progression and chemotherapy resistance and seems to be essential for the maintenance of cancer stem cells (CSC) in several tumor types. However, the interplay of these factors has not been fully addressed in bladder cancer. Here, our goal was to analyze the role of the Wnt/β-catenin pathway in paclitaxel resistance and to study the therapeutic efficacy of its inhibition in bladder cancer cells, as well as to determine its influence in the maintenance of the CSC-like phenotype in bladder cancer. Our results show that paclitaxel-resistant HT1197 cells have hyperactivation of the Wnt/β-catenin pathway and increased CSC-like properties compared with paclitaxel-sensitive 5637 cells. Paclitaxel sensitivity diminishes in 5637 cells after β-catenin overexpression or when they are grown as tumorspheres, enriched for the CSC-like phenotype. Additionally, downregulation of β-catenin or inhibition with XAV939 sensitizes HT1197 cells to paclitaxel. Moreover, a subset of muscle-invasive bladder carcinomas shows aberrant expression of β-catenin that associates with positive expression of the CSC marker ALDH1A1. In conclusion, we demonstrate that Wnt/β-catenin signaling contributes to paclitaxel resistance in bladder cancer cells with CSC-like properties.
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Affiliation(s)
- Rocío Jiménez-Guerrero
- Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Seville, Spain; (R.J.-G.); (M.G.-M.)
| | | | - M. Luz Flores
- Department of Pathology, Hospital Universitario de Badajoz, 06080 Badajoz, Spain;
| | - Mónica González-Moreno
- Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Seville, Spain; (R.J.-G.); (M.G.-M.)
| | | | - Francisco Romero
- Department of Microbiology, Faculty of Biology, Universidad de Sevilla, 41012 Seville, Spain; (A.B.-F.); (F.R.)
| | - Miguel Á. Japón
- Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Seville, Spain; (R.J.-G.); (M.G.-M.)
- Department of Pathology, Hospital Universitario Virgen del Rocío, 41013 Seville, Spain
- Correspondence: (M.Á.J.); (C.S.); Tel.: +34-955013027 (M.Á.J.); +34-955923091 (C.S.); Fax: +34-955923101 (C.S.)
| | - Carmen Sáez
- Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Seville, Spain; (R.J.-G.); (M.G.-M.)
- Department of Pathology, Hospital Universitario Virgen del Rocío, 41013 Seville, Spain
- Correspondence: (M.Á.J.); (C.S.); Tel.: +34-955013027 (M.Á.J.); +34-955923091 (C.S.); Fax: +34-955923101 (C.S.)
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